rs2228529

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.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. 16/21 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:13

Conservation

PhyloP100: 0.104

Publications

57 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=0.003504604).

BP6

Variant 10-49459059-T-C is Benign according to our data. Variant chr10-49459059-T-C is described in ClinVar as Benign. ClinVar VariationId is 129020.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.4238A>G	p.Gln1413Arg	missense_variant	Exon 21 of 21	ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001346440.2 link	c.4238A>G	p.Gln1413Arg	missense_variant	Exon 21 of 21		NP_001333369.1	Q03468-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 link	c.4238A>G	p.Gln1413Arg	missense_variant	Exon 21 of 21	1	NM_000124.4	ENSP00000348089.5		Q03468-1

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

GnomAD2 exomes

AF:

0.217

AC:

54373

AN:

251060

AF XY:

0.228

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 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

African (AFR)

AF:

0.119

AC:

3993

AN:

33480

American (AMR)

AF:

0.176

AC:

7853

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.261

AC:

6826

AN:

26136

East Asian (EAS)

AF:

0.0533

AC:

2116

AN:

39700

South Asian (SAS)

AF:

0.346

AC:

29815

AN:

86258

European-Finnish (FIN)

AF:

0.268

AC:

14317

AN:

53420

Middle Eastern (MID)

AF:

0.263

AC:

1517

AN:

5768

European-Non Finnish (NFE)

AF:

0.205

AC:

227612

AN:

1112008

Other (OTH)

AF:

0.208

AC:

12558

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

16838

33676

50513

67351

84189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7680

15360

23040

30720

38400

<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:

0.193

AC:

29445

AN:

152174

Hom.:

3281

Cov.:

AF XY:

0.201

AC XY:

14952

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.123

AC:

5103

AN:

41536

American (AMR)

AF:

0.208

AC:

3178

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.274

AC:

951

AN:

3468

East Asian (EAS)

AF:

0.0518

AC:

268

AN:

5178

South Asian (SAS)

AF:

0.347

AC:

1672

AN:

4820

European-Finnish (FIN)

AF:

0.283

AC:

2989

AN:

10578

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.216

AC:

14668

AN:

67986

Other (OTH)

AF:

0.210

AC:

444

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1205

2411

3616

4822

6027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.208

Hom.:

8533

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:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

PreventionGenetics, part of Exact Sciences

Significance: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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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. -

Nov 15, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: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

0.069

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.48

CADD

Benign

2.1

(source)

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

PhyloP100

0.10

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

Mutation Taster

=99/1

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