rs2228529

Variant summary

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

The NM_000124.4(ERCC6):c.4238A>G(p.Gln1413Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,614,064 control chromosomes in the GnomAD database, including 37,755 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1413Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.19 ( 3281 hom., cov: 32)

Exomes 𝑓: 0.21 ( 34474 hom. )

Consequence

ERCC6
NM_000124.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.104

Variant links:

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

ERCC6 links:

(HGNC:):

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=0.003504604).

BP6

Variant 10-49459059-T-C is Benign according to our data. Variant chr10-49459059-T-C is described in ClinVar as [Benign]. Clinvar id is 129020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49459059-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4 linkuse as main transcript	c.4238A>G	p.Gln1413Arg	missense_variant	21/21	ENST00000355832.10
ERCC6	NM_001346440.2 linkuse as main transcript	c.4238A>G	p.Gln1413Arg	missense_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10 linkuse as main transcript	c.4238A>G	p.Gln1413Arg	missense_variant	21/21	1	NM_000124.4	P1	Q03468-1
	ENST00000423283.1 linkuse as main transcript	n.235-13644T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.194

AC:

29433

AN:

152058

Hom.:

3277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.274

Gnomad EAS

AF:

0.0516

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.283

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.213

GnomAD3 exomes

AF:

0.217

AC:

54373

AN:

251060

Hom.:

6679

AF XY:

0.228

AC XY:

30986

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.259

Gnomad EAS exome

AF:

0.0523

Gnomad SAS exome

AF:

0.347

Gnomad FIN exome

AF:

0.275

Gnomad NFE exome

AF:

0.219

Gnomad OTH exome

AF:

0.231

GnomAD4 exome

AF:

0.210

AC:

306607

AN:

1461890

Hom.:

34474

Cov.:

AF XY:

0.215

AC XY:

156589

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.119

Gnomad4 AMR exome

AF:

0.176

Gnomad4 ASJ exome

AF:

0.261

Gnomad4 EAS exome

AF:

0.0533

Gnomad4 SAS exome

AF:

0.346

Gnomad4 FIN exome

AF:

0.268

Gnomad4 NFE exome

AF:

0.205

Gnomad4 OTH exome

AF:

0.208

GnomAD4 genome

AF:

0.193

AC:

29445

AN:

152174

Hom.:

3281

Cov.:

AF XY:

0.201

AC XY:

14952

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.123

Gnomad4 AMR

AF:

0.208

Gnomad4 ASJ

AF:

0.274

Gnomad4 EAS

AF:

0.0518

Gnomad4 SAS

AF:

0.347

Gnomad4 FIN

AF:

0.283

Gnomad4 NFE

AF:

0.216

Gnomad4 OTH

AF:

0.210

Alfa

AF:

0.210

Hom.:

6167

Bravo

AF:

0.178

TwinsUK

AF:

0.204

AC:

758

ALSPAC

AF:

0.192

AC:

739

ESP6500AA

AF:

0.135

AC:

596

ESP6500EA

AF:

0.217

AC:

1864

ExAC

AF:

0.218

AC:

26450

Asia WGS

AF:

0.180

AC:

628

AN:

3478

EpiCase

AF:

0.219

EpiControl

AF:

0.218

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Jun 29, 2012	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

COFS syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cockayne syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular degeneration

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.48

Cadd

Benign

2.1

Dann

Benign

0.62

DEOGEN2

Benign

0.081

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Benign

0.16

Sift

Benign

0.51

Sift4G

Benign

0.49

Polyphen

0.13

Vest4

0.034

MPC

0.12

ClinPred

0.0011

GERP RS

-4.9

Varity_R

0.023

gMVP

0.23

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