rs4253132

Positions:

Variant summary

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

The NM_000124.4(ERCC6):c.1821+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,613,440 control chromosomes in the GnomAD database, including 628,903 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.85 ( 55046 hom., cov: 32)

Exomes 𝑓: 0.89 ( 573857 hom. )

Consequence

ERCC6
NM_000124.4 splice_region, intron

Scores

Splicing: ADA: 0.0003081

Clinical Significance

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

Conservation

PhyloP100: -0.575

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 10-49493110-G-A is Benign according to our data. Variant chr10-49493110-G-A is described in ClinVar as [Benign]. Clinvar id is 190153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49493110-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.1821+7C>T		splice_region_variant, intron_variant		ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001346440.2 linkuse as main transcript	c.1821+7C>T		splice_region_variant, intron_variant			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.1821+7C>T		splice_region_variant, intron_variant		1	NM_000124.4	ENSP00000348089.5		Q03468-1

Frequencies

GnomAD3 genomes

AF:

0.847

AC:

128803

AN:

152040

Hom.:

55027

Cov.:

show subpopulations

Gnomad AFR

AF:

0.726

Gnomad AMI

AF:

0.828

Gnomad AMR

AF:

0.909

Gnomad ASJ

AF:

0.840

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.944

Gnomad FIN

AF:

0.898

Gnomad MID

AF:

0.896

Gnomad NFE

AF:

0.880

Gnomad OTH

AF:

0.870

GnomAD3 exomes

AF:

0.895

AC:

224491

AN:

250832

Hom.:

100929

AF XY:

0.899

AC XY:

121841

AN XY:

135582

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.938

Gnomad ASJ exome

AF:

0.841

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.937

Gnomad FIN exome

AF:

0.899

Gnomad NFE exome

AF:

0.882

Gnomad OTH exome

AF:

0.896

GnomAD4 exome

AF:

0.885

AC:

1293823

AN:

1461282

Hom.:

573857

Cov.:

AF XY:

0.887

AC XY:

644744

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.718

Gnomad4 AMR exome

AF:

0.934

Gnomad4 ASJ exome

AF:

0.844

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.936

Gnomad4 FIN exome

AF:

0.897

Gnomad4 NFE exome

AF:

0.881

Gnomad4 OTH exome

AF:

0.879

GnomAD4 genome

AF:

0.847

AC:

128870

AN:

152158

Hom.:

55046

Cov.:

AF XY:

0.853

AC XY:

63445

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.725

Gnomad4 AMR

AF:

0.909

Gnomad4 ASJ

AF:

0.840

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.944

Gnomad4 FIN

AF:

0.898

Gnomad4 NFE

AF:

0.880

Gnomad4 OTH

AF:

0.871

Alfa

AF:

0.874

Hom.:

70037

Bravo

AF:

0.841

Asia WGS

AF:

0.958

AC:

3332

AN:

3478

EpiCase

AF:

0.886

EpiControl

AF:

0.884

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Apr 17, 2012	- -
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	-	- -

not provided

Benign:2

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	- -

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

- -

Macular degeneration

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

DE SANCTIS-CACCHIONE SYNDROME

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.46

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00031

dbscSNV1_RF

Benign

0.0040

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