Two deletions in cis

[Laura Arnaldo]

Dear HGVS Nomenclature Committee,

I would like to submit an inquiry regarding the correct way to report a complex variant in the ERCC2 gene.

In our sample, two deletions are located in cis (as shown in the image).

Since ERCC2 is transcribed from the reverse strand, the first variant encountered in the cDNA sequence is a single-nucleotide deletion at position 1448 (c.1448del), which is expected to cause a frameshift at the protein level. The second variant is a 6-nucleotide deletion (c.1454_1459del), which would otherwise be in-frame on its own.

At the DNA level, we understand that these should be reported as two separate variants in allele phase and not as a delins: c.[1448del;1454_1459del]. Could you please confirm if this notation is correct?

Our main question concerns the protein-level nomenclature. While the frameshift is initiated by the first deletion, because both variants are in cis, the actual translation frame and the location of the premature stop codon depend on the combined sequence resulting from both deletions rather than the original sequence.

Given this combined effect, we are uncertain whether this should be reported as a single delins at the protein level—for example, p.(Met483_Arg487delinsArgArgGlyfsTer9)—or if another nomenclature convention should be applied in this scenario.

Thank you very much in advance for your time and assistance. We look forward to your guidance.

Kind regards,

Laura

[Johan den Dunnen]

Dear Laura,

please note essential information is missing, you do not give the reference sequence used. My guess is you used NM_000400.4.

Indeed, following current HGVS nomenclature recommendations the variant can be described as NC_000019.10:g.[45357291_45357296del;45357301del] NM_000400.4:c.[1448del;1454_1459del]. However, especially since the first variant creates a frame shift, it is allowed to merge the two variant descriptions and use NC_000019.10:g.45357290_45357301delinsCGTC NM_000400.4:c.1448_1459delinsGACG. For both formats, the description of the predicted consequence at protein level is the same, p.(Met483ArgfsTer9). I do agree this description is debatable since the current HGVS recommendations for the description at protein level are not unequivocal. The descriptions I get from tools like Mutalyzer and Variant Validator (p.(Met483ArgfsTer15)) can not be correct. I think in your description "Ter9" is not correct.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op maandag 31 augustus 2026 om 14:52:40 UTC+2 schreef laurarn...@gmail.com:

[Johan den Dunnen]

Dear Laura,

apologies, I made a mistake in the description of the variant. Correct is NC_000019.10:g.45357291_45357301delinsCGTC NM_000400.4:c.1448_1458delinsGACG, I missed the first/last nucleotide from the inserted sequence. Predictions of Mutalyzer and Variant Validator now agree with the predicted consequences p.(Met483ArgfsTer9).

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op donderdag 10 september 2026 om 14:55:42 UTC+2 schreef Johan den Dunnen: