rs368728467

Positions:

• chr10-49474074-A-G
• chr10-49474074-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000124.4(ERCC6):​c.2551T>C​(p.Trp851Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 10-49474074-A-G is Pathogenic according to our data. Variant chr10-49474074-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49474074-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.2551T>C	p.Trp851Arg	missense_variant	13/21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2	c.2551T>C	p.Trp851Arg	missense_variant	13/21		NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.2551T>C	p.Trp851Arg	missense_variant	13/21	1	NM_000124.4	ENSP00000348089	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cockayne syndrome type 2 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 24, 2015	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 851 of the ERCC6 protein (p.Trp851Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia-related phenotypes and/or Cockayne syndrome (PMID: 9443879, 29572252, 29915382, 32557569). ClinVar contains an entry for this variant (Variation ID: 210955). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ERCC6 protein function. Experimental studies have shown that this missense change affects ERCC6 function (PMID: 9443879, 20122405, 25820262, 29203878). For these reasons, this variant has been classified as Pathogenic. -

Cockayne syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Feb 23, 2022

Variant summary: ERCC6 c.2551T>C (p.Trp851Arg) results in a non-conservative amino acid change located in the Helicase, C-terminal domain (IPR001650) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251280 control chromosomes (gnomAD). c.2551T>C has been reported in the literature in individuals affected with Cockayne Syndrome or Cerebellar ataxia (Mallery_1998, Calmels_2018, Sun_2018). These data indicate that the variant may be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in impaired in its ability to associate with chromatin in response to UV irradiation, failed to suppress the increase in 53BP1 and Rif1 damage foci formation in CSB-knockout cells and failed to recruit BRCA1 (Mallery_1998, Lake_2010, Batenburg_2015, Batenburg_2019). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Uncertain significance, flagged submission

clinical testing

Counsyl

Mar 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.90		Gain of disorder (P = 0.0253);
MVP		0.94
MPC		0.69
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs368728467; hg19: chr10-50682120;