rs238406

Positions:

chr19-45365051-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000400.4(ERCC2):c.468A>C(p.Arg156=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,612,802 control chromosomes in the GnomAD database, including 265,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 32867 hom., cov: 33)

Exomes 𝑓: 0.56 ( 232819 hom. )

Consequence

ERCC2
NM_000400.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.83

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 19-45365051-T-G is Benign according to our data. Variant chr19-45365051-T-G is described in ClinVar as [Benign]. Clinvar id is 256021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45365051-T-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.861 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.468A>C	p.Arg156=	synonymous_variant	6/23	ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10 linkuse as main transcript	c.468A>C	p.Arg156=	synonymous_variant	6/23	1	NM_000400.4	ENSP00000375809	P1	P18074-1

Frequencies

GnomAD3 genomes

AF:

0.641

AC:

97410

AN:

152066

Hom.:

32816

Cov.:

show subpopulations

Gnomad AFR

AF:

0.869

Gnomad AMI

AF:

0.569

Gnomad AMR

AF:

0.529

Gnomad ASJ

AF:

0.588

Gnomad EAS

AF:

0.497

Gnomad SAS

AF:

0.589

Gnomad FIN

AF:

0.594

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.600

GnomAD3 exomes

AF:

0.580

AC:

144875

AN:

249946

Hom.:

42942

AF XY:

0.577

AC XY:

78082

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.877

Gnomad AMR exome

AF:

0.517

Gnomad ASJ exome

AF:

0.605

Gnomad EAS exome

AF:

0.509

Gnomad SAS exome

AF:

0.599

Gnomad FIN exome

AF:

0.596

Gnomad NFE exome

AF:

0.557

Gnomad OTH exome

AF:

0.561

GnomAD4 exome

AF:

0.562

AC:

820439

AN:

1460618

Hom.:

232819

Cov.:

AF XY:

0.563

AC XY:

409020

AN XY:

726670

show subpopulations

Gnomad4 AFR exome

AF:

0.882

Gnomad4 AMR exome

AF:

0.515

Gnomad4 ASJ exome

AF:

0.596

Gnomad4 EAS exome

AF:

0.490

Gnomad4 SAS exome

AF:

0.603

Gnomad4 FIN exome

AF:

0.593

Gnomad4 NFE exome

AF:

0.550

Gnomad4 OTH exome

AF:

0.571

GnomAD4 genome

AF:

0.641

AC:

97513

AN:

152184

Hom.:

32867

Cov.:

AF XY:

0.638

AC XY:

47443

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.869

Gnomad4 AMR

AF:

0.529

Gnomad4 ASJ

AF:

0.588

Gnomad4 EAS

AF:

0.497

Gnomad4 SAS

AF:

0.589

Gnomad4 FIN

AF:

0.594

Gnomad4 NFE

AF:

0.553

Gnomad4 OTH

AF:

0.599

Alfa

AF:

0.591

Hom.:

19855

Bravo

AF:

0.647

Asia WGS

AF:

0.562

AC:

1958

AN:

3478

EpiCase

AF:

0.565

EpiControl

AF:

0.559

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 -

Xeroderma pigmentosum, group D

Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	Genome-Nilou Lab	Jul 30, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 27888704, 25209577, 15896456, 18230301) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.68

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