rs4253196

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000124.4(ERCC6):c.2599-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,344,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ERCC6
NM_000124.4 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 0.350

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 Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 10-49473613-T-C is Pathogenic according to our data. Variant chr10-49473613-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190162.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.2599-26A>G		intron_variant		ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001346440.2 linkuse as main transcript	c.2599-26A>G		intron_variant			NP_001333369.1	Q03468-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 linkuse as main transcript	c.2599-26A>G		intron_variant		1	NM_000124.4	ENSP00000348089.5		Q03468-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251018

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000113

AC:

135

AN:

1191978

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

606666

show subpopulations

Gnomad4 AFR exome

AF:

0.0000712

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:

0.000150

Gnomad4 OTH exome

AF:

0.0000583

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000769

Hom.:

Bravo

AF:

0.0000642

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cockayne syndrome type 2

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic mutation in a patient with suspected diagnosis of Cockayne syndrome. Heterozygotes are expected to be asymptomatic carriers. -
Pathogenic, criteria provided, single submitter	clinical testing	Claritas Genomics	Apr 17, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Mar 02, 2020	This variant has been previously reported as a compound heterozygous change in five individuals and as a homozygous change in one individual with Cockayne Syndrome (PMID: 19894250, 29572252). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0053% (15/282404) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.2599-26A>G variant is classified as Likely 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 15, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change falls in intron 13 of the ERCC6 gene. It does not directly change the encoded amino acid sequence of the ERCC6 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs4253196, gnomAD 0.01%). This variant has been observed in individual(s) with Cockayne syndrome (PMID: 19894250, 27004399, 29572252). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 190162). Studies have shown that this variant results in partial insertion of intron 13 into the mRNA and introduces a premature termination codon (PMID: 9443879, 29572252). The resulting mRNA is expected to undergo nonsense-mediated decay. 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

Jun 03, 2022

Variant summary: ERCC6 c.2599-26A>G is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3 acceptor site. At least two publications report experimental evidence that this variant affects mRNA splicing and results in a 25-bp insertion corresponding to the end of intron 13, predicted as p.Met867ThrfsX14. The variant allele was found at a frequency of 5.2e-05 in 251018 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ERCC6 causing Cockayne Syndrome (5.2e-05 vs 0.0016), allowing no conclusion about variant significance. c.2599-26A>G has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Cockayne Syndrome (Mallery_1998, Laugel_2010, Calmels_2018). These data indicate that the variant is very likely to be associated with disease. 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 pathogenic. -

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

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Counsyl

Apr 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.67

BranchPoint Hunter

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

1.0

Position offset: -1

DS_AL_spliceai

0.68

Position offset: -26

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