rs4253196
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
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 (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
ERCC6
NM_000124.4 intron
NM_000124.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.350
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 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.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.81).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC6 | NM_000124.4 | c.2599-26A>G | intron_variant | ENST00000355832.10 | |||
ERCC6 | NM_001346440.2 | c.2599-26A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC6 | ENST00000355832.10 | c.2599-26A>G | intron_variant | 1 | NM_000124.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000518 AC: 13AN: 251018Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135638
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GnomAD4 exome AF: 0.000113 AC: 135AN: 1191978Hom.: 0 Cov.: 17 AF XY: 0.000119 AC XY: 72AN XY: 606666
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cockayne syndrome type 2 Pathogenic:3
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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Claritas Genomics | Apr 17, 2012 | - - |
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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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
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Name
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BayesDel_noAF
Benign
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Dann
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -1
DS_AL_spliceai
Position offset: -26
Find out detailed SpliceAI scores and Pangolin per-transcript scores at