rs2228526

Positions:

chr10-49470671-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000124.4(ERCC6):c.3289A>G(p.Met1097Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,613,762 control chromosomes in the GnomAD database, including 37,824 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3321 hom., cov: 32)

Exomes 𝑓: 0.21 ( 34503 hom. )

Consequence

ERCC6
NM_000124.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.201

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:

ERCC6 (HGNC:):

ERCC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 10-49470671-T-C is Benign according to our data. Variant chr10-49470671-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49470671-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	Protein	UniProt
ERCC6	NM_000124.4 linkuse as main transcript	c.3289A>G	p.Met1097Val	missense_variant	18/21	ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001346440.2 linkuse as main transcript	c.3289A>G	p.Met1097Val	missense_variant	18/21		NP_001333369.1	Q03468-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 linkuse as main transcript	c.3289A>G	p.Met1097Val	missense_variant	18/21	1	NM_000124.4	ENSP00000348089.5		Q03468-1

Frequencies

GnomAD3 genomes

AF:

0.195

AC:

29692

AN:

152042

Hom.:

3317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.208

Gnomad ASJ

AF:

0.274

Gnomad EAS

AF:

0.0514

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.282

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.213

GnomAD3 exomes

AF:

0.217

AC:

54486

AN:

251018

Hom.:

6691

AF XY:

0.229

AC XY:

31038

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.130

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:

0.276

Gnomad NFE exome

AF:

0.219

Gnomad OTH exome

AF:

0.231

GnomAD4 exome

AF:

0.210

AC:

306775

AN:

1461602

Hom.:

34503

Cov.:

AF XY:

0.215

AC XY:

156659

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.124

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:

0.195

AC:

29705

AN:

152160

Hom.:

3321

Cov.:

AF XY:

0.203

AC XY:

15080

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.129

Gnomad4 AMR

AF:

0.208

Gnomad4 ASJ

AF:

0.274

Gnomad4 EAS

AF:

0.0515

Gnomad4 SAS

AF:

0.347

Gnomad4 FIN

AF:

0.282

Gnomad4 NFE

AF:

0.216

Gnomad4 OTH

AF:

0.210

Alfa

AF:

0.208

Hom.:

7378

Bravo

AF:

0.180

TwinsUK

AF:

0.204

AC:

756

ALSPAC

AF:

0.191

AC:

737

ESP6500AA

AF:

0.140

AC:

619

ESP6500EA

AF:

0.217

AC:

1864

ExAC

AF:

0.218

AC:

26533

Asia WGS

AF:

0.181

AC:

629

AN:

3478

EpiCase

AF:

0.219

EpiControl

AF:

0.218

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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	-	- -
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	Eurofins Ntd Llc (ga)	Dec 05, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Claritas Genomics	Jun 29, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 17438655) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

0.056

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.1

DANN

Benign

0.64

DEOGEN2

Benign

0.042

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.22

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

0.32

REVEL

Benign

0.14

Sift

Benign

0.52

Sift4G

Benign

0.55

Polyphen

0.0010

Vest4

0.063

MPC

0.10

ClinPred

0.00087

GERP RS

-6.2

Varity_R

0.022

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: 1

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