rs3916876

Positions:

• chr19-45353263-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000400.4(ERCC2):​c.1737C>T​(p.Val579=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000639 in 1,613,878 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V579V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (9 hom.)
• Consequence: ERCC2 NM_000400.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.386

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-45353263-G-A is Benign according to our data. Variant chr19-45353263-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.386 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000598 (874/1461772) while in subpopulation AMR AF= 0.0126 (563/44714). AF 95% confidence interval is 0.0117. There are 9 homozygotes in gnomad4_exome. There are 409 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC2	NM_000400.4	c.1737C>T	p.Val579=	synonymous_variant	18/23	ENST00000391945.10
ERCC2	XM_011526611.3	c.1659C>T	p.Val553=	synonymous_variant	17/22
ERCC2	XR_001753633.3	n.1770C>T		non_coding_transcript_exon_variant	18/24
ERCC2	XR_007066680.1	n.1692C>T		non_coding_transcript_exon_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10	c.1737C>T	p.Val579=	synonymous_variant	18/23	1	NM_000400.4	P1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 151988 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00225 AC: 565 AN: 251286 Hom.: 5 AF XY: 0.00190 AC XY: 258 AN XY: 135844

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000598 AC: 874 AN: 1461772 Hom.: 9 Cov.: 33 AF XY: 0.000562 AC XY: 409 AN XY: 727202

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.000655

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152106 Hom.: 1 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74360

Gnomad4 AFR AF: 0.000651

Gnomad4 AMR AF: 0.00726

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000317 Hom.: 1

Bravo AF: 0.00154

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ERCC2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Xeroderma pigmentosum, group D;C1853102:Cerebrooculofacioskeletal syndrome 2;C1866504:Trichothiodystrophy 1, photosensitive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 10, 2022

- -

Xeroderma pigmentosum, group D Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.30
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3916876; hg19: chr19-45856521; COSMIC: COSV104702586; COSMIC: COSV104702586;