chr19-45352761-C-G

Position:

chr19-45352761-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000400.4(ERCC2):c.1887G>C(p.Gln629His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: 3.21

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]

ERCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a region_of_interest Mediates interaction with MMS19 (size 199) in uniprot entity ERCC2_HUMAN there are 29 pathogenic changes around while only 7 benign (81%) in NM_000400.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21362054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ERCC2	NM_000400.4 linkuse as main transcript	c.1887G>C	p.Gln629His	missense_variant	20/23	ENST00000391945.10
ERCC2	XM_011526611.3 linkuse as main transcript	c.1809G>C	p.Gln603His	missense_variant	19/22
ERCC2	XR_001753633.3 linkuse as main transcript	n.1920G>C		non_coding_transcript_exon_variant	20/24
ERCC2	XR_007066680.1 linkuse as main transcript	n.1842G>C		non_coding_transcript_exon_variant	19/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10 linkuse as main transcript	c.1887G>C	p.Gln629His	missense_variant	20/23	1	NM_000400.4	P1	P18074-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251194

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000800

AC:

117

AN:

1461752

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000737

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000138

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group D

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 15, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

Xeroderma pigmentosum

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Nov 16, 2021

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

Cerebrooculofacioskeletal syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 17, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Trichothiodystrophy 1, photosensitive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Cerebrooculofacioskeletal syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 629 of the ERCC2 protein (p.Gln629His). This variant is present in population databases (rs200665173, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134099). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ERCC2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;D;D

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.4

L;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.3

D;D;.

REVEL

Pathogenic

0.73

Sift

Benign

0.031

D;D;.

Sift4G

Benign

0.089

T;T;T

Polyphen

0.74

P;P;.

Vest4

0.58

MutPred

0.34

Loss of MoRF binding (P = 0.1496);.;.;

MVP

0.97

MPC

0.75

ClinPred

0.22

GERP RS

2.9

Varity_R

0.69

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

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.

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