rs34517175

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The ENST00000391945.10(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
ENST00000391945.10 missense, splice_region

Scores

8
9
2
Splicing: ADA: 0.6820
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:1

Conservation

PhyloP100: 7.21
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1
In a region_of_interest Mediates interaction with MMS19 (size 199) in uniprot entity ERCC2_HUMAN there are 31 pathogenic changes around while only 7 benign (82%) in ENST00000391945.10
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 id is 134100.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1, not_provided=1}.
BS2
High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERCC2NM_000400.4 linkuse as main transcriptc.1904C>T p.Ala635Val missense_variant, splice_region_variant 21/23 ENST00000391945.10 NP_000391.1
ERCC2XM_011526611.3 linkuse as main transcriptc.1826C>T p.Ala609Val missense_variant, splice_region_variant 20/22 XP_011524913.1
ERCC2XR_001753633.3 linkuse as main transcriptn.1937C>T splice_region_variant, non_coding_transcript_exon_variant 21/24
ERCC2XR_007066680.1 linkuse as main transcriptn.1859C>T splice_region_variant, non_coding_transcript_exon_variant 20/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERCC2ENST00000391945.10 linkuse as main transcriptc.1904C>T p.Ala635Val missense_variant, splice_region_variant 21/231 NM_000400.4 ENSP00000375809 P1P18074-1

Frequencies

GnomAD3 genomes
AF:
0.000651
AC:
99
AN:
152166
Hom.:
1
Cov.:
32
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
GnomAD3 exomes
AF:
0.00162
AC:
407
AN:
250822
Hom.:
3
AF XY:
0.00150
AC XY:
204
AN XY:
135768
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 SAS 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.:
8
Cov.:
37
AF XY:
0.000624
AC XY:
454
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00364
Gnomad4 ASJ exome
AF:
0.0198
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000105
Gnomad4 OTH exome
AF:
0.00176
GnomAD4 genome
AF:
0.000651
AC:
99
AN:
152166
Hom.:
1
Cov.:
32
AF XY:
0.000552
AC XY:
41
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000785
Gnomad4 ASJ
AF:
0.0210
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00144
Alfa
AF:
0.00114
Hom.:
1
Bravo
AF:
0.000899
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00128
AC:
11
ExAC
AF:
0.00115
AC:
140
EpiCase
AF:
0.000491
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024ERCC2: PP3, BS1, BS2 -
Xeroderma pigmentosum, group D Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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
Benign, criteria provided, single submittercurationSema4, Sema4Jul 28, 2020- -
ERCC2-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 22, 2020This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Uncertain
0.060
T
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.74
D;D;D
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Benign
0.016
T;T;T
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Uncertain
2.3
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-3.8
D;D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
0.99
D;D;.
Vest4
0.90
MVP
0.98
MPC
0.55
ClinPred
0.077
T
GERP RS
4.7
Varity_R
0.70
gMVP
0.68

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

LitVar

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

Other links and lift over

dbSNP: rs34517175; hg19: chr19-45855906; COSMIC: COSV67267427; COSMIC: COSV67267427; API