rs3916876

Positions:

chr19-45353263-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000400.4(ERCC2):c.1737C>T(p.Val579Val) 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 (★★).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 9 hom. )

Consequence

ERCC2
NM_000400.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.386

Variant links:

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]

ERCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 allele frequency = 0.00104 (158/152106) while in subpopulation AMR AF= 0.00726 (111/15286). AF 95% confidence interval is 0.00617. There are 1 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. 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	Protein	UniProt
ERCC2	NM_000400.4 link	c.1737C>T	p.Val579Val	synonymous_variant	18/23	ENST00000391945.10	NP_000391.1	P18074-1
ERCC2	XM_011526611.3 link	c.1659C>T	p.Val553Val	synonymous_variant	17/22		XP_011524913.1
ERCC2	XR_001753633.3 link	n.1770C>T		non_coding_transcript_exon_variant	18/24
ERCC2	XR_007066680.1 link	n.1692C>T		non_coding_transcript_exon_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10 link	c.1737C>T	p.Val579Val	synonymous_variant	18/23	1	NM_000400.4	ENSP00000375809.4		P18074-1

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

158

AN:

151988

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00190

AC XY:

258

AN XY:

135844

show subpopulations

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.:

Cov.:

AF XY:

0.000562

AC XY:

409

AN XY:

727202

show subpopulations

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.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74360

show subpopulations

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.:

Bravo

AF:

0.00154

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ERCC2: BP4, BP7, BS1, BS2 -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over