rs1198241866
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000355832.10(ERCC6):c.1009A>T(p.Lys337Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K337K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000355832.10 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ERCC6 | NM_000124.4 | c.1009A>T | p.Lys337Ter | stop_gained | 5/21 | ENST00000355832.10 | NP_000115.1 | |
ERCC6 | NM_001277058.2 | c.1009A>T | p.Lys337Ter | stop_gained | 5/6 | ENST00000447839.7 | NP_001263987.1 | |
ERCC6 | NM_001346440.2 | c.1009A>T | p.Lys337Ter | stop_gained | 5/21 | NP_001333369.1 | ||
ERCC6 | NM_001277059.2 | c.1009A>T | p.Lys337Ter | stop_gained | 5/6 | NP_001263988.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ERCC6 | ENST00000355832.10 | c.1009A>T | p.Lys337Ter | stop_gained | 5/21 | 1 | NM_000124.4 | ENSP00000348089 | P1 | |
ERCC6 | ENST00000447839.7 | c.1009A>T | p.Lys337Ter | stop_gained | 5/6 | 2 | NM_001277058.2 | ENSP00000387966 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251420Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cerebrooculofacioskeletal syndrome 1;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0751038:Cockayne syndrome type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 09, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 26, 2018 | This sequence change creates a premature translational stop signal (p.Lys337*) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 9443879, 18628313). This variant has been observed in an individual affected with Cockayne syndrome (PMID: 1339317). This variant is not present in population databases (ExAC no frequency). - |
Cockayne syndrome type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2021 | The p.Lys337X variant in ERCC6 has been reported in a compound heterozygous state in an individual with Cockayne syndrome, who carried a second pathogenic variant in ERCC6 (Troelstra 1992 PMID: 1339317, Schmickel 1977 PMID: 887325). It has also been identified in 1/113716 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID 550722). This nonsense variant leads to a premature termination codon at position 337, which is predicted to lead to a truncated or absent protein. Loss of function of the ERCC6 gene is an established disease mechanism in autosomal recessive Cockayne syndrome. An animal model in ERCC6 has shown that a similar variant causes some features of Cockayne Syndrome including photosensitivity, but only mild deficits in growth and neurologic function (van Der Horst 1997 PMID: 9150142). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cockayne syndrome. ACMG/AMP criteria applied: PVS1, PM2_Suporting, PM3, PS3_Moderate. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at