rs4253013

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000124.4(ERCC6):c.411G>A(p.Leu137=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 1,613,920 control chromosomes in the GnomAD database, including 8,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1174 hom., cov: 33)

Exomes 𝑓: 0.081 ( 7669 hom. )

Consequence

ERCC6
NM_000124.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.372

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 10-49532554-C-T is Benign according to our data. Variant chr10-49532554-C-T is described in ClinVar as [Benign]. Clinvar id is 129019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49532554-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.372 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ERCC6	NM_000124.4 linkuse as main transcript	c.411G>A	p.Leu137=	synonymous_variant	2/21	ENST00000355832.10
ERCC6	NM_001277058.2 linkuse as main transcript	c.411G>A	p.Leu137=	synonymous_variant	2/6	ENST00000447839.7
ERCC6	NM_001346440.2 linkuse as main transcript	c.411G>A	p.Leu137=	synonymous_variant	2/21
ERCC6	NM_001277059.2 linkuse as main transcript	c.411G>A	p.Leu137=	synonymous_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10 linkuse as main transcript	c.411G>A	p.Leu137=	synonymous_variant	2/21	1	NM_000124.4	P1	Q03468-1
ERCC6	ENST00000447839.7 linkuse as main transcript	c.411G>A	p.Leu137=	synonymous_variant	2/6	2	NM_001277058.2		P0DP91-1

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15639

AN:

152108

Hom.:

1175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.0747

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0638

Gnomad OTH

AF:

0.110

GnomAD3 exomes

AF:

0.128

AC:

32050

AN:

251180

Hom.:

3461

AF XY:

0.118

AC XY:

16077

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.0781

Gnomad EAS exome

AF:

0.402

Gnomad SAS exome

AF:

0.0960

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0619

Gnomad OTH exome

AF:

0.0981

GnomAD4 exome

AF:

0.0813

AC:

118907

AN:

1461694

Hom.:

7669

Cov.:

AF XY:

0.0810

AC XY:

58873

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.104

Gnomad4 AMR exome

AF:

0.253

Gnomad4 ASJ exome

AF:

0.0792

Gnomad4 EAS exome

AF:

0.347

Gnomad4 SAS exome

AF:

0.0965

Gnomad4 FIN exome

AF:

0.109

Gnomad4 NFE exome

AF:

0.0612

Gnomad4 OTH exome

AF:

0.0936

GnomAD4 genome

AF:

0.103

AC:

15652

AN:

152226

Hom.:

1174

Cov.:

AF XY:

0.108

AC XY:

8001

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.106

Gnomad4 AMR

AF:

0.171

Gnomad4 ASJ

AF:

0.0747

Gnomad4 EAS

AF:

0.385

Gnomad4 SAS

AF:

0.105

Gnomad4 FIN

AF:

0.114

Gnomad4 NFE

AF:

0.0638

Gnomad4 OTH

AF:

0.112

Alfa

AF:

0.0719

Hom.:

280

Bravo

AF:

0.111

Asia WGS

AF:

0.242

AC:

843

AN:

3478

EpiCase

AF:

0.0622

EpiControl

AF:

0.0598

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Jun 11, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2018	- -

COFS syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cerebrooculofacioskeletal syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cockayne syndrome type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cockayne syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

UV-sensitive syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

DE SANCTIS-CACCHIONE SYNDROME

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Macular degeneration

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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