10-49530737-G-A

Position:

chr10-49530737-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000124.4(ERCC6):c.526C>T(p.Arg176*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R176R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

ERCC6
NM_000124.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.26

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 10-49530737-G-A is Pathogenic according to our data. Variant chr10-49530737-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC6	NM_000124.4 linkuse as main transcript	c.526C>T	p.Arg176*	stop_gained	3/21	ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001277058.2 linkuse as main transcript	c.526C>T	p.Arg176*	stop_gained	3/6	ENST00000447839.7	NP_001263987.1	P0DP91-1A8K4Q3
ERCC6	NM_001346440.2 linkuse as main transcript	c.526C>T	p.Arg176*	stop_gained	3/21		NP_001333369.1	Q03468-1
ERCC6	NM_001277059.2 linkuse as main transcript	c.526C>T	p.Arg176*	stop_gained	3/6		NP_001263988.1	P0DP91-1A8K4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 linkuse as main transcript	c.526C>T	p.Arg176*	stop_gained	3/21	1	NM_000124.4	ENSP00000348089.5		Q03468-1
ERCC6	ENST00000447839.7 linkuse as main transcript	c.526C>T	p.Arg176*	stop_gained	3/6	2	NM_001277058.2	ENSP00000387966.2		P0DP91-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251268

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461212

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2023	This sequence change creates a premature translational stop signal (p.Arg176*) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is present in population databases (rs771781694, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of Cockayne syndrome (PMID: 25356239, 29572252). ClinVar contains an entry for this variant (Variation ID: 551532). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24700531, 25356239) -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 14, 2017

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2023

The c.526C>T (p.R176*) alteration, located in exon 3 (coding exon 2) of the ERCC6 gene, consists of a C to T substitution at nucleotide position 526. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 176. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.003% (8/282646) total alleles studied. The highest observed frequency was 0.01% (3/30604) of South Asian alleles. This variant has been reported to be homozygous or compound heterozygous in multiple individuals with features consistent with ERCC6-related disorders (Luo, 2014; Calmels, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

Cockayne syndrome type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The stop gained variant c.526C>T (p.Arg176Ter) in ERCC6 gene has been reported previously in homozygous state in patients affected with Cockayne syndrome (Luo et al., 2014). The p.Arg176Ter variant is reported with the allele frequency (0.002%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The nucleotide change in ERCC6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic -

Cockayne syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 08, 2024

Variant summary: ERCC6 c.526C>T (p.Arg176X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 251268 control chromosomes. c.526C>T has been reported in the literature in the homozyougs and compound heterozygous state in individuals affected with Cockayne Syndrome (Calmels_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29572252). ClinVar contains an entry for this variant (Variation ID: 551532). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

Vest4

0.90

GERP RS

4.2

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