19-45357368-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP3BS1_SupportingBS2

The NM_000400.4(ERCC2):c.1381C>G(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: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 9 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:4O:1

Conservation

PhyloP100: 8.35

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 Likely_benign. Variant got -2 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.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000492 (75/152356) while in subpopulation SAS AF= 0.00705 (34/4826). AF 95% confidence interval is 0.00518. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4 link	c.1381C>G	p.Leu461Val	missense_variant	Exon 15 of 23	ENST00000391945.10	NP_000391.1	P18074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10 link	c.1381C>G	p.Leu461Val	missense_variant	Exon 15 of 23	1	NM_000400.4	ENSP00000375809.4		P18074-1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000411

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00120

AC:

302

AN:

251138

Hom.:

AF XY:

0.00153

AC XY:

207

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00712

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000379

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000895

AC:

1308

AN:

1461292

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

809

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00696

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000510

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.000492

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00705

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000411

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000625

Hom.:

Bravo

AF:

0.000287

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00133

AC:

162

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

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

Jan 01, 1997

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

May 13, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

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

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ERCC2: PP3, BS3:Supporting, BS1 -

Jun 04, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1Other:1

Aug 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Trichothiodystrophy 1, photosensitive

Pathogenic:1

Jan 01, 1997

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Xeroderma pigmentosum

Uncertain:1

Oct 11, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Inborn genetic diseases

Benign:1

Mar 15, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;T;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.4

M;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.4

N;N;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.98

D;D;.

Vest4

0.96

MVP

0.87

MPC

0.62

ClinPred

0.16

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.75

Position offset: -1

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