rs121913016
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2
The NM_000400.4(ERCC2):āc.1381C>Gā(p.Leu461Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000857 in 1,613,648 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00049 ( 0 hom., cov: 32)
Exomes š: 0.00090 ( 9 hom. )
Consequence
ERCC2
NM_000400.4 missense
NM_000400.4 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 8.35
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 Likely_benign. Variant got -1 ACMG points.
PM1
In a region_of_interest Mediates interaction with MMS19 (size 199) in uniprot entity ERCC2_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_000400.4
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
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 | c.1381C>G | p.Leu461Val | missense_variant | 15/23 | ENST00000391945.10 | NP_000391.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ERCC2 | ENST00000391945.10 | c.1381C>G | p.Leu461Val | missense_variant | 15/23 | 1 | NM_000400.4 | ENSP00000375809 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000493 AC: 75AN: 152238Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
75
AN:
152238
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00120 AC: 302AN: 251138Hom.: 2 AF XY: 0.00153 AC XY: 207AN XY: 135730
GnomAD3 exomes
AF:
AC:
302
AN:
251138
Hom.:
AF XY:
AC XY:
207
AN XY:
135730
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000895 AC: 1308AN: 1461292Hom.: 9 Cov.: 31 AF XY: 0.00111 AC XY: 809AN XY: 726946
GnomAD4 exome
AF:
AC:
1308
AN:
1461292
Hom.:
Cov.:
31
AF XY:
AC XY:
809
AN XY:
726946
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000492 AC: 75AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.000523 AC XY: 39AN XY: 74502
GnomAD4 genome
AF:
AC:
75
AN:
152356
Hom.:
Cov.:
32
AF XY:
AC XY:
39
AN XY:
74502
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
4
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
162
Asia WGS
AF:
AC:
8
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:5Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Xeroderma pigmentosum, group D Pathogenic:2Uncertain:3
Likely pathogenic, flagged submission | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 14, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, flagged submission | literature only | OMIM | Jan 01, 1997 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 13, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PP5. - |
Uncertain significance, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_000400.3:c.1381C>G in the ERCC2 gene has an allele frequency of 0.007 in South Asian subpopulation in the gnomAD database. The functional study (GM436 cells) demenstrated Leu461Val exits in apparent absence of expression of the other XPD allele. Hence, the Leu461Val allele can be assumed not to interfere with the essential function of the XPD (ERCC2) gene product (PMID: 7849702). Takayama et al reported a patient with typical trichothiodystrophy characteristics, harboring Leu461Val and a deletion of amino acids 716-730 in one allele and Ala725Pro in the other allele; the pathogenicity of Ala725Pro, however, is not determined (PMID: 9195225). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP3. - |
not provided Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 04, 2023 | Published functional studies of the A717G;L461V complex allele demonstrated a reduced TFIIH binding capacity with partial NER activity compared to wild-type, but no functional data for Leu461Val on its own exist (Horibata et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 15982307, 18470933, 23221806, 10064601, 24728327, 22234153, 8571952, 12116233, 10447254, 23232694, 19681155, 9238033, 26884178, 7849702, 7585650, 9195225, 12393803, 16135823, 12820975, 27504877, 29607586, 30136158, 34426522, 31980526, 26556299, 25716912, 31589614, 33726816, 36253817, 37179334) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ERCC2: PP3, BS1:Supporting, BS3:Supporting - |
not specified Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 01, 2024 | Variant summary: ERCC2 c.1381C>G (p.Leu461Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251138 control chromosomes, predominantly at a frequency of 0.0071 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum phenotype (0.00061), strongly suggesting that the variant is benign. c.1381C>G has been reported in the literature always a complex allele in cis with c.2150C>G (p.Ala717Gly) in compound heterozygous genotypes with other pathogenic alleles in multiple individuals with features of Xeroderma Pigmentosum and Trichothiodystrophy (example, Takayama_1996, Moslehi_2012, Fujimoto_2005, Zhou_2013, Fassihi_2016, Horibata_2015). This complex allele has also been reported in individuals with various cancers, although these findings have not been ascertained in the context of this evaluation. These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Xeroderma Pigmentosum/Trichothiodystrophy. At least one publication reports experimental evidence evaluating an impact on protein function (Horibata_2015). These results showed no damaging effect of this variant in isolation, as it possessed full Nucleotide Excision Repair (NER) activity (comparable to p.WT). The following publications have been ascertained in the context of this evaluation (PMID: 26884178, 9238033, 8571952, 23232694, 22234153, 15982307, 25716912, 7585650). ClinVar contains an entry for this variant (Variation ID: 16779). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Trichothiodystrophy 1, photosensitive Pathogenic:1
Pathogenic, flagged submission | literature only | OMIM | Jan 01, 1997 | - - |
Xeroderma pigmentosum Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 11, 2021 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 15, 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;D
Polyphen
D;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at