rs4253211

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3689G>C(p.Arg1230Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0905 in 1,613,988 control chromosomes in the GnomAD database, including 7,410 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1230C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.065 ( 433 hom., cov: 32)

Exomes 𝑓: 0.093 ( 6977 hom. )

Consequence

ERCC6
NM_000124.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.542

Publications

56 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=0.0027070343).

BP6

Variant 10-49470271-C-G is Benign according to our data. Variant chr10-49470271-C-G is described in ClinVar as Benign. ClinVar VariationId is 129018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4 link	c.3689G>C	p.Arg1230Pro	missense_variant	Exon 18 of 21	ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001346440.2 link	c.3689G>C	p.Arg1230Pro	missense_variant	Exon 18 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.3689G>C	p.Arg1230Pro	missense_variant	Exon 18 of 21	1	NM_000124.4	ENSP00000348089.5		Q03468-1

Frequencies

GnomAD3 genomes

AF:

0.0647

AC:

9846

AN:

152124

Hom.:

434

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0204

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0459

Gnomad ASJ

AF:

0.0804

Gnomad EAS

AF:

0.0804

Gnomad SAS

AF:

0.0364

Gnomad FIN

AF:

0.0456

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0985

Gnomad OTH

AF:

0.0694

GnomAD2 exomes

AF:

0.0712

AC:

17882

AN:

251302

AF XY:

0.0712

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.0352

Gnomad ASJ exome

AF:

0.0764

Gnomad EAS exome

AF:

0.0690

Gnomad FIN exome

AF:

0.0508

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.0787

GnomAD4 exome

AF:

0.0931

AC:

136149

AN:

1461746

Hom.:

6977

Cov.:

AF XY:

0.0916

AC XY:

66580

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.0180

AC:

602

AN:

33472

American (AMR)

AF:

0.0384

AC:

1716

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0776

AC:

2029

AN:

26132

East Asian (EAS)

AF:

0.101

AC:

4012

AN:

39692

South Asian (SAS)

AF:

0.0425

AC:

3663

AN:

86246

European-Finnish (FIN)

AF:

0.0547

AC:

2921

AN:

53418

Middle Eastern (MID)

AF:

0.0945

AC:

545

AN:

5768

European-Non Finnish (NFE)

AF:

0.104

AC:

115607

AN:

1111906

Other (OTH)

AF:

0.0837

AC:

5054

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

6862

13724

20585

27447

34309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4222

8444

12666

16888

21110

<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:

0.0646

AC:

9837

AN:

152242

Hom.:

433

Cov.:

AF XY:

0.0602

AC XY:

4480

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0203

AC:

845

AN:

41552

American (AMR)

AF:

0.0459

AC:

702

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0804

AC:

279

AN:

3470

East Asian (EAS)

AF:

0.0801

AC:

415

AN:

5184

South Asian (SAS)

AF:

0.0365

AC:

176

AN:

4826

European-Finnish (FIN)

AF:

0.0456

AC:

483

AN:

10598

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0985

AC:

6698

AN:

67998

Other (OTH)

AF:

0.0672

AC:

142

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

468

936

1403

1871

2339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<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:

0.0822

Hom.:

436

Bravo

AF:

0.0632

TwinsUK

AF:

0.107

AC:

397

ALSPAC

AF:

0.108

AC:

417

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.0962

AC:

827

ExAC

AF:

0.0731

AC:

8879

EpiCase

AF:

0.0955

EpiControl

AF:

0.0952

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2012

Claritas Genomics

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.6

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.13

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

PhyloP100

-0.54

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.3

REVEL

Benign

0.18

Sift

Benign

0.14

Sift4G

Benign

0.30

Polyphen

0.0010

Vest4

0.12

MPC

0.15

ClinPred

0.0048

GERP RS

-7.1

Varity_R

0.22

gMVP

0.28

Mutation Taster

=71/29

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