19-45357368-G-C

Variant names:

• chr19-45357368-G-C
• rs121913016
• NM_000400.4:c.1381C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L461P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (9 hom.)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5 B:4 O:1
• Conservation: PhyloP100: 8.35
• Publications: 27 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-45357368-G-C is Benign according to our data. Variant chr19-45357368-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16779.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	NM_000400.4	MANE Select	c.1381C>G	p.Leu461Val	missense	Exon 15 of 23	NP_000391.1
	ERCC2	NM_001440355.1		c.1309C>G	p.Leu437Val	missense	Exon 15 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.1303C>G	p.Leu435Val	missense	Exon 14 of 22	NP_001427285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.1381C>G	p.Leu461Val	missense	Exon 15 of 23	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.1381C>G	p.Leu461Val	missense	Exon 15 of 22	ENSP00000375808.4
	ERCC2	ENST00000391941.6	TSL:1	c.1309C>G	p.Leu437Val	missense	Exon 14 of 21	ENSP00000375805.2

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152238 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00120 AC: 302 AN: 251138 AF XY: 0.00153

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 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.: 9 Cov.: 31 AF XY: 0.00111 AC XY: 809 AN XY: 726946

African (AFR) AF: 0.000149 AC: 5 AN: 33464

American (AMR) AF: 0.000224 AC: 10 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00696 AC: 600 AN: 86234

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000510 AC: 567 AN: 1111494

Other (OTH) AF: 0.000944 AC: 57 AN: 60380

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000523 AC XY: 39 AN XY: 74502

African (AFR) AF: 0.000144 AC: 6 AN: 41594

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000411 AC: 28 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.000287

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Xeroderma pigmentosum, group D Pathogenic:2 Uncertain:3

Jan 01, 1997

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

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.

Apr 14, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

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.

not provided Uncertain:1 Benign:2

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

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

not specified Benign:1 Other: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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.96
MVP		0.87
MPC		0.62
ClinPred		0.16	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.79
Mutation Taster		=21/79	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913016; hg19: chr19-45860626; COSMIC: COSV105931169; COSMIC: COSV105931169;