10-49470323-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

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:14

Conservation

PhyloP100: 1.71

Publications

61 publications found

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 Gene-Disease associations (from GenCC):

Cockayne spectrum with or without cerebrooculofacioskeletal syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Cockayne syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Orphanet, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
UV-sensitive syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
COFS syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
UV-sensitive syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
premature ovarian failure 11
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ERCC6 links:

ENSG00000235939 (HGNC:):

ENSG00000235939 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 129017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ERCC6	NM_000124.4 link	c.3637A>G	p.Arg1213Gly	missense_variant	Exon 18 of 21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2 link	c.3637A>G	p.Arg1213Gly	missense_variant	Exon 18 of 21		NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 link	c.3637A>G	p.Arg1213Gly	missense_variant	Exon 18 of 21	1	NM_000124.4	ENSP00000348089.5

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

GnomAD2 exomes

AF:

0.218

AC:

54918

AN:

251392

AF XY:

0.230

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 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

African (AFR)

AF:

0.140

AC:

4691

AN:

33478

American (AMR)

AF:

0.177

AC:

7922

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

6864

AN:

26132

East Asian (EAS)

AF:

0.0534

AC:

2118

AN:

39696

South Asian (SAS)

AF:

0.346

AC:

29835

AN:

86246

European-Finnish (FIN)

AF:

0.268

AC:

14320

AN:

53420

Middle Eastern (MID)

AF:

0.274

AC:

1579

AN:

5768

European-Non Finnish (NFE)

AF:

0.205

AC:

227988

AN:

1111996

Other (OTH)

AF:

0.210

AC:

12704

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

15184

30368

45552

60736

75920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7704

15408

23112

30816

38520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.200

AC:

30429

AN:

152218

Hom.:

3435

Cov.:

AF XY:

0.207

AC XY:

15394

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.145

AC:

6006

AN:

41532

American (AMR)

AF:

0.209

AC:

3201

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

955

AN:

3470

East Asian (EAS)

AF:

0.0516

AC:

268

AN:

5194

South Asian (SAS)

AF:

0.347

AC:

1676

AN:

4828

European-Finnish (FIN)

AF:

0.282

AC:

2985

AN:

10570

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.216

AC:

14704

AN:

68000

Other (OTH)

AF:

0.217

AC:

460

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1237

2475

3712

4950

6187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.211

Hom.:

5836

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:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 29, 2012

Claritas Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

not provided

Benign:3

Oct 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17119055, 20220177, 9443879)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

COFS syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cockayne syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Macular degeneration

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

1.7

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.22

Sift

Benign

0.12

Sift4G

Benign

0.12

Vest4

0.16

ClinPred

0.027

GERP RS

1.9

Varity_R

0.12

gMVP

0.33

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over