rs2228528

Variant names:

Variant summary

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

The NM_000124.4(ERCC6):c.1196G>A(p.Gly399Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,613,894 control chromosomes in the GnomAD database, including 27,994 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2775 hom., cov: 32)

Exomes 𝑓: 0.18 ( 25219 hom. )

Consequence

ERCC6
NM_000124.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.139

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:

PGBD3 (HGNC:19400): (piggyBac transposable element derived 3) This gene is a member of a small family of genes derived from piggyBac transposable elements. The encoded protein contains a zinc-ribbon domain characteristic of transposon-derived proteins and may function as a regulator of transcription. Alternative splicing occurs between a splice site from exon 5 of the adjacent upstream gene 'excision repair cross-complementation group 6' (ERCC6, GeneID: 2074) and the 3' splice site upstream of the open reading frame (ORF) of this gene, 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. Pseudogenes for this gene are defined on chromosomes 4, 5 and 12. [provided by RefSeq, Mar 2016]

PGBD3 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=1.4212728E-4).

BP6

Variant 10-49524234-C-T is Benign according to our data. Variant chr10-49524234-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49524234-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4 link	c.1196G>A	p.Gly399Asp	missense_variant	Exon 5 of 21	ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001277058.2 link	c.1196G>A	p.Gly399Asp	missense_variant	Exon 5 of 6	ENST00000447839.7	NP_001263987.1	P0DP91-1A8K4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 link	c.1196G>A	p.Gly399Asp	missense_variant	Exon 5 of 21	1	NM_000124.4	ENSP00000348089.5		Q03468-1
ERCC6	ENST00000447839.7 link	c.1196G>A	p.Gly399Asp	missense_variant	Exon 5 of 6	2	NM_001277058.2	ENSP00000387966.2		P0DP91-1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27169

AN:

151926

Hom.:

2773

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.149

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.465

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.160

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.184

GnomAD3 exomes

AF:

0.202

AC:

50252

AN:

248904

Hom.:

6246

AF XY:

0.192

AC XY:

25860

AN XY:

134730

show subpopulations

Gnomad AFR exome

AF:

0.172

Gnomad AMR exome

AF:

0.301

Gnomad ASJ exome

AF:

0.155

Gnomad EAS exome

AF:

0.471

Gnomad SAS exome

AF:

0.139

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.162

Gnomad OTH exome

AF:

0.178

GnomAD4 exome

AF:

0.176

AC:

256860

AN:

1461850

Hom.:

25219

Cov.:

AF XY:

0.174

AC XY:

126222

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.167

Gnomad4 AMR exome

AF:

0.293

Gnomad4 ASJ exome

AF:

0.157

Gnomad4 EAS exome

AF:

0.449

Gnomad4 SAS exome

AF:

0.139

Gnomad4 FIN exome

AF:

0.164

Gnomad4 NFE exome

AF:

0.165

Gnomad4 OTH exome

AF:

0.181

GnomAD4 genome

AF:

0.179

AC:

27188

AN:

152044

Hom.:

2775

Cov.:

AF XY:

0.179

AC XY:

13269

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.167

Gnomad4 AMR

AF:

0.220

Gnomad4 ASJ

AF:

0.155

Gnomad4 EAS

AF:

0.464

Gnomad4 SAS

AF:

0.142

Gnomad4 FIN

AF:

0.160

Gnomad4 NFE

AF:

0.162

Gnomad4 OTH

AF:

0.184

Alfa

AF:

0.171

Hom.:

6178

Bravo

AF:

0.187

TwinsUK

AF:

0.169

AC:

625

ALSPAC

AF:

0.180

AC:

692

ESP6500AA

AF:

0.165

AC:

729

ESP6500EA

AF:

0.161

AC:

1382

ExAC

AF:

0.196

AC:

23759

Asia WGS

AF:

0.296

AC:

1029

AN:

3478

EpiCase

AF:

0.157

EpiControl

AF:

0.155

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

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. -

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

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2012

Claritas Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2015

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

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25026993, 20044625) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Cerebrooculofacioskeletal syndrome 1

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cockayne syndrome type 2

Benign:1

Jul 30, 2021

Genome-Nilou Lab

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

- -

UV-sensitive syndrome 1

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DE SANCTIS-CACCHIONE SYNDROME

Benign:1

Jul 30, 2021

Genome-Nilou Lab

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

0.075

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.050

DANN

Benign

0.50

DEOGEN2

Benign

0.041

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.33

T;.;T

MetaRNN

Benign

0.00014

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.37

N;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

1.2

N;N;N

REVEL

Benign

0.013

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.019

MPC

0.13

ClinPred

0.00046

GERP RS

-3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.017

gMVP

0.11

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