rs34517175

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP3BP4_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

8
9
2
Splicing: ADA: 0.6820
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O: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 was made for transcript

Our verdict: Benign. The variant received -10 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 NM_000400.4
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 id is 134100.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_benign=2, Benign=2}.
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 FAILED quality control check.
BS2
High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERCC2NM_000400.4 linkc.1904C>T p.Ala635Val missense_variant, splice_region_variant Exon 21 of 23 ENST00000391945.10 NP_000391.1 P18074-1
ERCC2XM_011526611.3 linkc.1826C>T p.Ala609Val missense_variant, splice_region_variant Exon 20 of 22 XP_011524913.1
ERCC2XR_001753633.3 linkn.1937C>T splice_region_variant, non_coding_transcript_exon_variant Exon 21 of 24
ERCC2XR_007066680.1 linkn.1859C>T splice_region_variant, non_coding_transcript_exon_variant Exon 20 of 23

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERCC2ENST00000391945.10 linkc.1904C>T p.Ala635Val missense_variant, splice_region_variant Exon 21 of 23 1 NM_000400.4 ENSP00000375809.4 P18074-1

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
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.:
8
Cov.:
37
AF XY:
0.000624
AC XY:
454
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
AC:
4
AN:
33480
Gnomad4 AMR exome
AF:
0.00364
AC:
163
AN:
44724
Gnomad4 ASJ exome
AF:
0.0198
AC:
517
AN:
26136
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39700
Gnomad4 SAS exome
AF:
0.0000348
AC:
3
AN:
86256
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53182
Gnomad4 NFE exome
AF:
0.000105
AC:
117
AN:
1112010
Gnomad4 Remaining exome
AF:
0.00176
AC:
106
AN:
60392
Heterozygous variant carriers
0
70
139
209
278
348
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
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:
99
AN:
152166
Hom.:
1
Cov.:
32
AF XY:
0.000552
AC XY:
41
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000483
AC:
0.0000482509
AN:
0.0000482509
Gnomad4 AMR
AF:
0.000785
AC:
0.00078534
AN:
0.00078534
Gnomad4 ASJ
AF:
0.0210
AC:
0.0210375
AN:
0.0210375
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.000132
AC:
0.00013233
AN:
0.00013233
Gnomad4 OTH
AF:
0.00144
AC:
0.00143541
AN:
0.00143541
Heterozygous variant carriers
0
5
10
16
21
26
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
3
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: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 v4.3

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;.;.
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
Mutation Taster
=28/72
disease causing

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