rs34917815

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000124.4(ERCC6):c.4065T>G(p.Asp1355Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,613,900 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1355V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

ERCC6
NM_000124.4 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0420

Publications

5 publications found

Variant links:

COSMIC-nc: COSV104674036

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027449727).

BP6

Variant 10-49459232-A-C is Benign according to our data. Variant chr10-49459232-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0023 (350/152214) while in subpopulation AFR AF = 0.00761 (316/41538). AF 95% confidence interval is 0.00692. There are 1 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4 link	c.4065T>G	p.Asp1355Glu	missense_variant, splice_region_variant	Exon 21 of 21	ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001346440.2 link	c.4065T>G	p.Asp1355Glu	missense_variant, splice_region_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.4065T>G	p.Asp1355Glu	missense_variant, splice_region_variant	Exon 21 of 21	1	NM_000124.4	ENSP00000348089.5		Q03468-1

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00763

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000666

AC:

166

AN:

249396

AF XY:

0.000504

show subpopulations

Gnomad AFR exome

AF:

0.00673

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000170

Gnomad OTH exome

AF:

0.000982

GnomAD4 exome

AF:

0.000261

AC:

381

AN:

1461686

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

160

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00615

AC:

206

AN:

33478

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000764

AC:

AN:

1111962

Other (OTH)

AF:

0.000679

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00230

AC:

350

AN:

152214

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00761

AC:

316

AN:

41538

American (AMR)

AF:

0.00131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68002

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000720

Hom.:

Bravo

AF:

0.00253

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000700

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 28, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 10, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

3.3

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-0.91

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.61

M_CAP

Benign

0.030

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.85

MutationAssessor

Benign

2.0

PhyloP100

0.042

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.39

Sift

Benign

0.20

Sift4G

Benign

0.42

Polyphen

0.88

Vest4

0.18

MutPred

0.12

Gain of helix (P = 0.0425);

MVP

0.38

MPC

0.15

ClinPred

0.0091

GERP RS

-11

Varity_R

0.047

gMVP

0.24

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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