19-45364001-C-T

Position:

chr19-45364001-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000400.4(ERCC2):c.934G>A(p.Asp312Asn) variant causes a missense change. The variant allele was found at a frequency of 0.319 in 1,543,626 control chromosomes in the GnomAD database, including 83,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6406 hom., cov: 33)

Exomes 𝑓: 0.33 ( 77067 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 4.64

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:

ERCC2 (HGNC:):

ERCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015462935).

BP6

Variant 19-45364001-C-T is Benign according to our data. Variant chr19-45364001-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45364001-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC2	NM_000400.4 linkuse as main transcript	c.934G>A	p.Asp312Asn	missense_variant	10/23	ENST00000391945.10	NP_000391.1	P18074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10 linkuse as main transcript	c.934G>A	p.Asp312Asn	missense_variant	10/23	1	NM_000400.4	ENSP00000375809.4		P18074-1

Frequencies

GnomAD3 genomes

AF:

0.265

AC:

40248

AN:

152048

Hom.:

6409

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.513

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.0468

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.370

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.351

Gnomad OTH

AF:

0.273

GnomAD3 exomes

AF:

0.290

AC:

41034

AN:

141480

Hom.:

6833

AF XY:

0.301

AC XY:

23207

AN XY:

77124

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.195

Gnomad ASJ exome

AF:

0.363

Gnomad EAS exome

AF:

0.0431

Gnomad SAS exome

AF:

0.350

Gnomad FIN exome

AF:

0.369

Gnomad NFE exome

AF:

0.354

Gnomad OTH exome

AF:

0.321

GnomAD4 exome

AF:

0.325

AC:

452603

AN:

1391460

Hom.:

77067

Cov.:

AF XY:

0.328

AC XY:

225055

AN XY:

686616

show subpopulations

Gnomad4 AFR exome

AF:

0.102

Gnomad4 AMR exome

AF:

0.198

Gnomad4 ASJ exome

AF:

0.356

Gnomad4 EAS exome

AF:

0.0399

Gnomad4 SAS exome

AF:

0.350

Gnomad4 FIN exome

AF:

0.366

Gnomad4 NFE exome

AF:

0.342

Gnomad4 OTH exome

AF:

0.302

GnomAD4 genome

AF:

0.264

AC:

40240

AN:

152166

Hom.:

6406

Cov.:

AF XY:

0.264

AC XY:

19676

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.113

Gnomad4 AMR

AF:

0.229

Gnomad4 ASJ

AF:

0.352

Gnomad4 EAS

AF:

0.0467

Gnomad4 SAS

AF:

0.342

Gnomad4 FIN

AF:

0.370

Gnomad4 NFE

AF:

0.351

Gnomad4 OTH

AF:

0.269

Alfa

AF:

0.315

Hom.:

4031

Bravo

AF:

0.243

TwinsUK

AF:

0.361

AC:

1338

ALSPAC

AF:

0.339

AC:

1307

ESP6500AA

AF:

0.0976

AC:

387

ESP6500EA

AF:

0.317

AC:

2507

ExAC

AF:

0.213

AC:

21786

Asia WGS

AF:

0.168

AC:

589

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with cancer risk -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Xeroderma pigmentosum, group D

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2018	This variant is associated with the following publications: (PMID: 27306318, 24841663, 25916209, 24101192, 24933002, 23973729, 29989875, 27153395, 24868140, 11606376, 19041121, 24728327, 21245954, 19242824, 21643959, 19669592, 19055600, 18641418, 22184993, 14630517, 20070155, 19706757) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cerebrooculofacioskeletal syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Trichothiodystrophy 1, photosensitive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;T;.;.

Eigen

Benign

0.066

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D;D;D

MetaRNN

Benign

0.0015

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.8

D;D;.;D;.

REVEL

Benign

0.13

Sift

Benign

0.17

T;T;.;T;.

Sift4G

Benign

0.14

T;T;T;T;.

Polyphen

0.053

B;B;.;.;.

Vest4

0.23

MPC

0.28

ClinPred

0.018

GERP RS

5.2

Varity_R

0.59

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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