rs151242354

Variant names:

• chr10-49482689-G-A
• rs151242354
• NM_000124.4:c.2167C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-49482689-G-A
• chr10-49482689-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PP3_Moderate PP5_Very_Strong

The NM_000124.4(ERCC6):​c.2167C>T​(p.Gln723*) 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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Cockayne spectrum with or without cerebrooculofacioskeletal syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Cockayne syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Orphanet, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• UV-sensitive syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• UV-sensitive syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• premature ovarian failure 11

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP3: Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 190160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.2167C>T	p.Gln723*	stop_gained, splice_region_variant	Exon 10 of 21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2	c.2167C>T	p.Gln723*	stop_gained, splice_region_variant	Exon 10 of 21		NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.2167C>T	p.Gln723*	stop_gained, splice_region_variant	Exon 10 of 21	1	NM_000124.4	ENSP00000348089.5

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151928 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251352 AF XY: 0.0000662

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 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.: 0 Cov.: 31 AF XY: 0.000252 AC XY: 183 AN XY: 727018

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000345 AC: 383 AN: 1111608

Other (OTH) AF: 0.0000662 AC: 4 AN: 60384

GnomAD4 genome AF: 0.0000856 AC: 13 AN: 151928 Hom.: 0 Cov.: 31 AF XY: 0.0000944 AC XY: 7 AN XY: 74182

African (AFR) AF: 0.0000484 AC: 2 AN: 41332

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cockayne syndrome type 2 Pathogenic:5

Jan 07, 2013

Claritas Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Pathogenic:3

Oct 20, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 04, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Inborn genetic diseases Pathogenic:1

Jul 17, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Mar 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ERCC6-related disorder Pathogenic:1

Dec 10, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 20, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 26, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		10
Vest4		0.97
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs151242354; hg19: chr10-50690735;