chr4-5748262-G-GCAGC
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153717.3(EVC):c.1056_1059dup(p.Glu354SerfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
EVC
NM_153717.3 frameshift
NM_153717.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.596
Genes affected
EVC (HGNC:3497): (EvC ciliary complex subunit 1) This gene encodes a protein containing a leucine zipper and a transmembrane domain. This gene has been implicated in both Ellis-van Creveld syndrome (EvC) and Weyers acrodental dysostosis. [provided by RefSeq, Jul 2008]
CRMP1 (HGNC:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-5748262-G-GCAGC is Pathogenic according to our data. Variant chr4-5748262-G-GCAGC is described in ClinVar as [Pathogenic]. Clinvar id is 555774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EVC | NM_153717.3 | c.1056_1059dup | p.Glu354SerfsTer31 | frameshift_variant | 8/21 | ENST00000264956.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC | ENST00000264956.11 | c.1056_1059dup | p.Glu354SerfsTer31 | frameshift_variant | 8/21 | 1 | NM_153717.3 | P1 | |
EVC | ENST00000509451.1 | c.1056_1059dup | p.Glu354SerfsTer31 | frameshift_variant | 8/12 | 1 | |||
CRMP1 | ENST00000506216.5 | n.1697_1698insGCTG | non_coding_transcript_exon_variant | 13/13 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461884Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1AN XY: 727246
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ellis-van Creveld syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2017 | - - |
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2018 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in EVC are known to be pathogenic (PMID: 23220543). This variant has been observed in two individuals affected with Ellis-van Creveld syndrome (PMID: 23220543). ClinVar contains an entry for this variant (Variation ID: 555774). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu354Serfs*31) in the EVC gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at