dbSNP rs34517175: ERCC2:p.Ala635Val (chr19-45352648-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_000400.4(ERCC2):c.1904C>T(p.Ala635Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000626 in 1,613,814 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A635A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00065 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 8 hom. )

Consequence

ERCC2
NM_000400.4 missense, splice_region

Scores

Splicing: ADA: 0.6820

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O:1

Conservation

PhyloP100: 7.21

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

cerebrooculofacioskeletal syndrome 2
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
trichothiodystrophy 1, photosensitive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
xeroderma pigmentosum group D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P
sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
COFS syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
trichothiodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
xeroderma pigmentosum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
xeroderma pigmentosum-Cockayne syndrome complex
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ERCC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, REVEL, REVEL [when dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.015789181).

BP6

Variant 19-45352648-G-A is Benign according to our data. Variant chr19-45352648-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134100.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000623 (911/1461648) while in subpopulation AMR AF = 0.00364 (163/44724). AF 95% confidence interval is 0.00319. There are 8 homozygotes in GnomAdExome4. There are 454 alleles in the male GnomAdExome4 subpopulation. Median coverage is 37. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000400.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC2	NM_000400.4	MANE Select	c.1904C>T	p.Ala635Val	missense splice_region	Exon 21 of 23	NP_000391.1
ERCC2	NM_001440355.1		c.1832C>T	p.Ala611Val	missense splice_region	Exon 21 of 23	NP_001427284.1
ERCC2	NM_001440356.1		c.1826C>T	p.Ala609Val	missense splice_region	Exon 20 of 22	NP_001427285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.1904C>T	p.Ala635Val	missense splice_region	Exon 21 of 23	ENSP00000375809.4
ERCC2	ENST00000391944.8	TSL:1	c.1904C>T	p.Ala635Val	missense splice_region	Exon 21 of 22	ENSP00000375808.4
ERCC2	ENST00000391941.6	TSL:1	c.1832C>T	p.Ala611Val	missense splice_region	Exon 20 of 21	ENSP00000375805.2

Frequencies

GnomAD3 genomes

AF:

0.000651

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00162

AC:

407

AN:

250822

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.00448

Gnomad ASJ exome

AF:

0.0203

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000318

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000623

AC:

911

AN:

1461648

Hom.:

Cov.:

AF XY:

0.000624

AC XY:

454

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.00364

AC:

163

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0198

AC:

517

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53182

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000105

AC:

117

AN:

1112010

Other (OTH)

AF:

0.00176

AC:

106

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000651

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000552

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41450

American (AMR)

AF:

0.000785

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68012

Other (OTH)

AF:

0.00144

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.000899

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00115

AC:

140

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ERCC2: PP3, BS1, BS2

Xeroderma pigmentosum, group D

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Xeroderma pigmentosum

Benign:1

Jul 28, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

ERCC2-related disorder

Benign:1

May 22, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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

Benign:1

May 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.016

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.3

PhyloP100

7.2

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.99

Vest4

0.90

MVP

0.98

MPC

0.55

ClinPred

0.077

GERP RS

4.7

Varity_R

0.70

gMVP

0.68

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.68

dbscSNV1_RF

Benign

0.56

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over