rs1553812417
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_147127.5(EVC2):c.3634delinsGA(p.Leu1212AspfsTer53) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L1212L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 31)
Consequence
EVC2
NM_147127.5 frameshift
NM_147127.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.54
Genes affected
EVC2 (HGNC:19747): (EvC ciliary complex subunit 2) This gene encodes a protein that functions in bone formation and skeletal development. Mutations in this gene, as well as in a neighboring gene that lies in a head-to-head configuration, cause Ellis-van Creveld syndrome, an autosomal recessive skeletal dysplasia that is also known as chondroectodermal dysplasia. Mutations in this gene also cause acrofacial dysostosis Weyers type, also referred to as Curry-Hall syndrome, a disease that combines limb and facial abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-5565283-G-TC is Pathogenic according to our data. Variant chr4-5565283-G-TC is described in ClinVar as [Pathogenic]. Clinvar id is 455997.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EVC2 | NM_147127.5 | c.3634delinsGA | p.Leu1212AspfsTer53 | frameshift_variant | 21/22 | ENST00000344408.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC2 | ENST00000344408.10 | c.3634delinsGA | p.Leu1212AspfsTer53 | frameshift_variant | 21/22 | 1 | NM_147127.5 | P2 | |
EVC2 | ENST00000310917.6 | c.3394delinsGA | p.Leu1132AspfsTer53 | frameshift_variant | 21/22 | 1 | A2 | ||
EVC2 | ENST00000475313.5 | c.3394delinsGA | p.Leu1132AspfsTer30 | frameshift_variant, NMD_transcript_variant | 21/23 | 1 | |||
EVC2 | ENST00000509670.1 | c.*2027delinsGA | 3_prime_UTR_variant, NMD_transcript_variant | 22/23 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ellis-van Creveld syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 03, 2017 | This sequence change deletes 1 nucleotide and inserts 2 nucleotides in exon 21 of the EVC2 mRNA (c.3634delinsGA), causing a frameshift at codon 1212. This creates a premature translational stop signal in the last exon of the EVC2 mRNA (p.Leu1212Aspfs*53). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 97 amino acids of the EVC2 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a EVC2-related disease. A different truncation downstream of this variant (p.Ser1220Argfs*3) has been determined to be pathogenic (PMID: 12571802, 19810119). This suggests that deletion of this region of the EVC2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at