rs766980240

Variant names:

• chr10-49459235-C-G
• rs766980240
• NM_000124.4:c.4063-1G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-49459235-C-G
• chr10-49459235-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000124.4(ERCC6):​c.4063-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000889 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ERCC6 NM_000124.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.35

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]

ENSG00000235939 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PP5: Variant 10-49459235-C-G is Pathogenic according to our data. Variant chr10-49459235-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49459235-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.4063-1G>C		splice_acceptor_variant, intron_variant	Intron 20 of 20	ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2	c.4063-1G>C		splice_acceptor_variant, intron_variant	Intron 20 of 20		NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.4063-1G>C		splice_acceptor_variant, intron_variant	Intron 20 of 20	1	NM_000124.4	ENSP00000348089.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249272 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134946

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461678 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cockayne syndrome type 2 Pathogenic:4

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Department of Biochemistry, Faculty of Medicine, University of Khartoum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The splice acceptor variant c.4063-1G>C in the ERCC6 gene has been reported previously in homozygous state in individuals affected with Cockayne syndrome (Calmels et al., 2018; Laugel et al., 2010). This sequence change affects an acceptor splice site in intron 20 of the ERCC6 gene. This variant is reported with the allele frequency (0.002%) in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/ Likely Pathogenic. However study on multiple affected individuals and functional studies on the pathogenicity of the variant is unavailable. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

May 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change affects an acceptor splice site in intron 20 of the ERCC6 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs766980240, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with Cockayne syndrome (PMID: 19894250, 29572252). ClinVar contains an entry for this variant (Variation ID: 549960). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Mar 06, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebrooculofacioskeletal syndrome 1;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0751038:Cockayne syndrome type 2 Pathogenic:1

Jul 28, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.92		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs766980240; hg19: chr10-50667281;