rs151242354

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PP3_ModeratePP5_Very_Strong

The NM_000124.4(ERCC6):c.2167C>T(p.Gln723Ter) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,613,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

ERCC6
NM_000124.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 10.0

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 10-49482689-G-A is Pathogenic according to our data. Variant chr10-49482689-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4 linkuse as main transcript	c.2167C>T	p.Gln723Ter	stop_gained, splice_region_variant	10/21	ENST00000355832.10
ERCC6	NM_001346440.2 linkuse as main transcript	c.2167C>T	p.Gln723Ter	stop_gained, splice_region_variant	10/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10 linkuse as main transcript	c.2167C>T	p.Gln723Ter	stop_gained, splice_region_variant	10/21	1	NM_000124.4	P1	Q03468-1

Frequencies

GnomAD3 genomes

AF:

0.0000856

AC:

AN:

151928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251352

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000266

AC:

389

AN:

1461442

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

183

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000345

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000856

AC:

AN:

151928

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74182

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000176

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cockayne syndrome type 2

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Claritas Genomics	Jan 07, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to create a premature termination codon at position 723 in exon 10 (of 21) of ERCC6, p.(Gln723*). However, it has been demonstrated in RNA assays that this variant causes in-frame exon 10 skipping (p.Phe665_Gln723del) leading to the removal of the helical-like domain III, which the role of is not well-established (PMID: 29572252). The variant is present in a large population cohort at a frequency of 0.007%, which is consistent with a recessive condition (rs151242354, 20/282,734 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified as homozygous and compound heterozygous with a second pathogenic allele in multiple individuals with Cockayne syndrome spanning the full phenotype spectrum and mostly originating from the United Kingdom (PMID: 25326635, 29572252). Defective post-UV recovery of RNA synthesis has also been demonstrated in the cells of affected individuals (PMID: 29572252). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PVS1_Moderate, PM2, PP4. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. However only recessive inheritance has been reported for Cockayne syndrome, type B (OMIM) (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 10 of 21). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (22 heterozygous, 0 homozygous). (P) 0701 - Comparable variants also predicted to result in NMD, have very strong previous evidence for pathogenicity for Cockayne syndrome (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with Cockayne syndrome (ClinVar, Decipher, Laugel, V. et al. (2010)) (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found twice in our laboratory in trans with another pathogenic mutation in patients, including one with suspected diagnosis of Cockayne syndrome. Heterozygotes are expected to be asymptomatic carriers. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2022	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: 21228398, 19894250, 23311583, 25326635, 27356891, 29572252, 31980526) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Gln723*) 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 (rs151242354, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome (PMID: 19894250). ClinVar contains an entry for this variant (Variation ID: 190160). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 20, 2022	- -

Cerebrooculofacioskeletal syndrome 1;C0242379:Lung cancer;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0751038:Cockayne syndrome type 2;C3151063:Age related macular degeneration 5;C3551173:UV-sensitive syndrome 1;C4310783:Premature ovarian failure 11

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2023

The c.2167C>T (p.Q723*) alteration, located in exon 10 (coding exon 9) of the ERCC6 gene, consists of a C to T substitution at nucleotide position 2167. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 723. 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 0.007% (20/282734) total alleles studied. The highest observed frequency was 0.013% (17/129108) of European (non-Finnish) alleles. This variant has been reported to be homozygous or compound heterozygous in multiple individuals with features consistent with ERCC6-related disorders (Laugel, 2010; Calmels, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

ERCC6-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 10, 2018

The ERCC6 c.2167C>T (p.Gln723Ter) variant is a stop-gained in the splice region variant that is predicted to result in premature truncation of the protein. The p.Gln723Ter variant has been reported in two studies in which it is found in a total of 12 individuals affected with Cockayne syndrome-B, including in two in a homozygous state and in ten in a compound heterozygous state with a unique null variant (Laugel et al. 2010; Calmels et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. The p.Gln723Ter variant has not been reported in the literature in association with macular degeneration or cerebrooculofacioskeletal syndrome. Based on the collective evidence and the potential impact of stop-gained variants, the p.Gln723Ter variant is classified as pathogenic for ERCC6-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Cockayne syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 20, 2022

Variant summary: ERCC6 c.2167C>T (p.Gln723X) 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. Truncations downstream of this position have been classified as pathogenic (e.g. c.3862C>T (p.Arg1288X); c.2569C>T (p.Arg857X); ClinVar). The variant allele was found at a frequency of 6.4e-05 in 251352 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ERCC6 causing Cockayne Syndrome (6.4e-05 vs 0.0016). c.2167C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cockayne Syndrome and is seen primarily in individuals from the UK, suggesting a potential founder effect (e.g. Laugel_2010, Clamels_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Five laboratories classified the variant as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

DE SANCTIS-CACCHIONE SYNDROME

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Jun 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

A;A

Vest4

0.97

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: -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