rs2229760

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000124.4(ERCC6):c.2751C>T(p.Gly917Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,613,566 control chromosomes in the GnomAD database, including 122,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8661 hom., cov: 33)

Exomes 𝑓: 0.39 ( 113966 hom. )

Consequence

ERCC6
NM_000124.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.397

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:

ERCC6 (HGNC:):

ERCC6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 10-49472987-G-A is Benign according to our data. Variant chr10-49472987-G-A is described in ClinVar as [Benign]. Clinvar id is 129015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49472987-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.397 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC6	NM_000124.4 linkuse as main transcript	c.2751C>T	p.Gly917Gly	synonymous_variant	15/21	ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001346440.2 linkuse as main transcript	c.2751C>T	p.Gly917Gly	synonymous_variant	15/21		NP_001333369.1	Q03468-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 linkuse as main transcript	c.2751C>T	p.Gly917Gly	synonymous_variant	15/21	1	NM_000124.4	ENSP00000348089.5		Q03468-1

Frequencies

GnomAD3 genomes

AF:

0.315

AC:

47908

AN:

151970

Hom.:

8670

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.518

Gnomad AMR

AF:

0.311

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.318

Gnomad SAS

AF:

0.256

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.413

Gnomad OTH

AF:

0.331

GnomAD3 exomes

AF:

0.340

AC:

85285

AN:

250862

Hom.:

15553

AF XY:

0.345

AC XY:

46723

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.276

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.312

Gnomad SAS exome

AF:

0.245

Gnomad FIN exome

AF:

0.382

Gnomad NFE exome

AF:

0.411

Gnomad OTH exome

AF:

0.367

GnomAD4 exome

AF:

0.388

AC:

567413

AN:

1461478

Hom.:

113966

Cov.:

AF XY:

0.385

AC XY:

280045

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.137

Gnomad4 AMR exome

AF:

0.279

Gnomad4 ASJ exome

AF:

0.332

Gnomad4 EAS exome

AF:

0.311

Gnomad4 SAS exome

AF:

0.249

Gnomad4 FIN exome

AF:

0.383

Gnomad4 NFE exome

AF:

0.417

Gnomad4 OTH exome

AF:

0.365

GnomAD4 genome

AF:

0.315

AC:

47889

AN:

152088

Hom.:

8661

Cov.:

AF XY:

0.312

AC XY:

23175

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.140

Gnomad4 AMR

AF:

0.311

Gnomad4 ASJ

AF:

0.327

Gnomad4 EAS

AF:

0.318

Gnomad4 SAS

AF:

0.255

Gnomad4 FIN

AF:

0.377

Gnomad4 NFE

AF:

0.413

Gnomad4 OTH

AF:

0.329

Alfa

AF:

0.385

Hom.:

18389

Bravo

AF:

0.305

Asia WGS

AF:

0.273

AC:

949

AN:

3476

EpiCase

AF:

0.419

EpiControl

AF:

0.418

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 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

-0.70

CADD

Benign

4.3

DANN

Benign

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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