10-49470323-T-C

Position:

chr10-49470323-T-C

Variant summary

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

The NM_000124.4(ERCC6):c.3637A>G(p.Arg1213Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,614,068 control chromosomes in the GnomAD database, including 38,152 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3435 hom., cov: 33)

Exomes 𝑓: 0.21 ( 34717 hom. )

Consequence

ERCC6
NM_000124.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.71

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=0.005204171).

BP6

Variant 10-49470323-T-C is Benign according to our data. Variant chr10-49470323-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49470323-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.3637A>G	p.Arg1213Gly	missense_variant	18/21	ENST00000355832.10
ERCC6	NM_001346440.2 linkuse as main transcript	c.3637A>G	p.Arg1213Gly	missense_variant	18/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10 linkuse as main transcript	c.3637A>G	p.Arg1213Gly	missense_variant	18/21	1	NM_000124.4	P1	Q03468-1
	ENST00000423283.1 linkuse as main transcript	n.235-2380T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.200

AC:

30404

AN:

152100

Hom.:

3431

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.209

Gnomad ASJ

AF:

0.275

Gnomad EAS

AF:

0.0515

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.282

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.220

GnomAD3 exomes

AF:

0.218

AC:

54918

AN:

251392

Hom.:

6760

AF XY:

0.230

AC XY:

31235

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.172

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.0523

Gnomad SAS exome

AF:

0.347

Gnomad FIN exome

AF:

0.276

Gnomad NFE exome

AF:

0.220

Gnomad OTH exome

AF:

0.233

GnomAD4 exome

AF:

0.211

AC:

308021

AN:

1461850

Hom.:

34717

Cov.:

AF XY:

0.216

AC XY:

157242

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.140

Gnomad4 AMR exome

AF:

0.177

Gnomad4 ASJ exome

AF:

0.263

Gnomad4 EAS exome

AF:

0.0534

Gnomad4 SAS exome

AF:

0.346

Gnomad4 FIN exome

AF:

0.268

Gnomad4 NFE exome

AF:

0.205

Gnomad4 OTH exome

AF:

0.210

GnomAD4 genome

AF:

0.200

AC:

30429

AN:

152218

Hom.:

3435

Cov.:

AF XY:

0.207

AC XY:

15394

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.145

Gnomad4 AMR

AF:

0.209

Gnomad4 ASJ

AF:

0.275

Gnomad4 EAS

AF:

0.0516

Gnomad4 SAS

AF:

0.347

Gnomad4 FIN

AF:

0.282

Gnomad4 NFE

AF:

0.216

Gnomad4 OTH

AF:

0.217

Alfa

AF:

0.213

Hom.:

4648

Bravo

AF:

0.185

TwinsUK

AF:

0.204

AC:

758

ALSPAC

AF:

0.193

AC:

742

ESP6500AA

AF:

0.156

AC:

688

ESP6500EA

AF:

0.217

AC:

1870

ExAC

AF:

0.220

AC:

26752

Asia WGS

AF:

0.181

AC:

629

AN:

3478

EpiCase

AF:

0.220

EpiControl

AF:

0.219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Jun 29, 2012	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	This variant is associated with the following publications: (PMID: 17119055, 20220177, 9443879) -
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

0.092

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.29

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.22

Sift

Benign

0.12

Sift4G

Benign

0.12

Polyphen

0.65

Vest4

0.16

MPC

0.20

ClinPred

0.027

GERP RS

1.9

Varity_R

0.12

gMVP

0.33

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