rs121913026

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000400.4(ERCC2):c.2164C>T(p.Arg722Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 0.263

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

PP5

Variant 19-45352235-G-A is Pathogenic according to our data. Variant chr19-45352235-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45352235-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4 link	c.2164C>T	p.Arg722Trp	missense_variant	Exon 22 of 23	ENST00000391945.10	NP_000391.1	P18074-1
ERCC2	XM_011526611.3 link	c.2086C>T	p.Arg696Trp	missense_variant	Exon 21 of 22		XP_011524913.1
ERCC2	XR_001753633.3 link	n.2197C>T		non_coding_transcript_exon_variant	Exon 22 of 24
ERCC2	XR_007066680.1 link	n.2119C>T		non_coding_transcript_exon_variant	Exon 21 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10 link	c.2164C>T	p.Arg722Trp	missense_variant	Exon 22 of 23	1	NM_000400.4	ENSP00000375809.4		P18074-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251074

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000824

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that R722W disrupts RARB2 mRNA synthesis by deregulating several transcriptional steps and destabilizes the architecture of the evolutionarily conserved general transcription factor IIH (TFIIH) (Singh et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18817897, 25431422, 7920640, 15494306, 26577220, 23232694, 23221806, 23039039, 20944642, 25620205, 22705887, 12820975, 27862069, 8571952, 28724667, 19085937, 31282071, 31589614, 32732226, 31980526, 31803976) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 722 of the ERCC2 protein (p.Arg722Trp). This variant is present in population databases (rs121913026, gnomAD 0.004%). This missense change has been observed in individual(s) with photosensitive trichothiodystrophy (PMID: 31282071, 31803976). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16792). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ERCC2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Cerebrooculofacioskeletal syndrome 2

Pathogenic:3

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2014

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ERCC2-related disorder

Pathogenic:2

Feb 09, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ERCC2 c.2164C>T variant is predicted to result in the amino acid substitution p.Arg722Trp. This variant was reported in the homozygous and compound heterozygous states in individuals with trichothiodystrophy (TTD) (Pehlivan et al. 2012. PubMed ID: 23039039; Takayama et al. 1996. PubMed ID: 8571952; Botta et al. 2008. PubMed ID: 19085937; Usuda et al. 2011. PubMed ID: 20944642; Brauns et al. 2016. PubMed ID: 26577220; Miguet et al. 2016. PubMed ID: 27862069; Leemans et al. 2019. PubMed ID: 31803976). Functional studies of cells isolated from patients with this variant showed high sensitivity to UV light and decreased DNA repair (Takayama et al. 1996. PubMed ID: 8571952; Nishiwaki et al. 2008. PubMed ID: 18817897). A homozygous mouse model for the p.Arg772Trp variant showed an earlier on-set of age-related vascular phenotypes (Durik et al. 2012. PubMed ID: 22705887). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-45855493-G-A). This variant is interpreted as pathogenic. -

Nov 20, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a compound heterozygous and homozygous change in patients with trichothiodystrophy (PMID: 8571952, 19085937, 20944642, 23232694, 26577220). Functional studies using patient fibroblast cell lines show that this variant impedes the recruitment of transcription repair factor TFIIH to sites of DNA damage, at least in part by weakening the interaction of ERCC2 with the GTF2H2 subunit (PMID: 18817897, 25620205). Another study using patient fibroblast cells shows that this variant results in a drastic reduction in the expression of collagen type VI alpha1 subunit, an important component of soft connective tissues, due to impaired TFIIH function (PMID: 23221806). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/276898) and thus is presumed to be rare. The c.2164C>T (p.Arg722Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2164C>T (p.Arg722Trp) variant is classified as Pathogenic. -

Trichothiodystrophy 1, photosensitive

Pathogenic:2

Jun 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3+PM3_Strong+PP4+PM2_Supporting -

Trichothiodystrophy

Pathogenic:1

May 28, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ERCC2 c.2164C>T (p.Arg722Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251074 control chromosomes. c.2164C>T has been reported in the literature in individuals affected with Trichothiodystrophy (e.g. Takayama_1996, Taylor_1997, Usuda_2011, Zhou_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that p.Arg722Trp affected normal activity (e.g. Singh_2015). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Xeroderma pigmentosum, group D;C1853102:Cerebrooculofacioskeletal syndrome 2;C1866504:Trichothiodystrophy 1, photosensitive

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypotrichosis simplex

Pathogenic:1

Mar 05, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg722Trp variant in ERCC2 has been reported in >10 individuals with trichothiodystrophy (TTD) as homozygous or in trans with a second pathogenic ERCC2 variant (Takayama 1996 PMID:8571952, Stefanini 2010 PMID:19931493, Pehlivan 2012 PMID:23039039). It has also been identified in 0.005% (6/128882) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 16792). In vitro functional studies support an impact on protein function (Pehlivan 2012 PMID:23039039, Singh 2015 PMID:25620205). Mouse models have shown that this variant causes TTD (deBoer 1998 PMID: 9651581). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive TTD. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;T;T

Eigen

Benign

0.023

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.65

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

3.2

M;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.7

D;D;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.89

MVP

0.94

MPC

0.81

ClinPred

0.96

GERP RS

-5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.92

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

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