rs750396637
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_147127.5(EVC2):βc.3405_3411delβ(p.Gly1136ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,608,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P1135P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_147127.5 frameshift
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 | UniProt |
---|---|---|---|---|---|---|---|
EVC2 | NM_147127.5 | c.3405_3411del | p.Gly1136ArgfsTer6 | frameshift_variant | 20/22 | ENST00000344408.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC2 | ENST00000344408.10 | c.3405_3411del | p.Gly1136ArgfsTer6 | frameshift_variant | 20/22 | 1 | NM_147127.5 | P2 | |
EVC2 | ENST00000310917.6 | c.3165_3171del | p.Gly1056ArgfsTer6 | frameshift_variant | 20/22 | 1 | A2 | ||
EVC2 | ENST00000475313.5 | c.3165_3171del | p.Gly1056ArgfsTer6 | frameshift_variant, NMD_transcript_variant | 20/23 | 1 | |||
EVC2 | ENST00000509670.1 | c.*1798_*1804del | 3_prime_UTR_variant, NMD_transcript_variant | 21/23 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000124 AC: 3AN: 242236Hom.: 0 AF XY: 0.00000761 AC XY: 1AN XY: 131432
GnomAD4 exome AF: 0.0000494 AC: 72AN: 1456548Hom.: 0 AF XY: 0.0000442 AC XY: 32AN XY: 724492
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74292
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 03, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19810119, 29068549) - |
Jeune thoracic dystrophy Pathogenic:2
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 30, 2023 | This sequence change creates a premature translational stop signal (p.Gly1136Argfs*6) in the EVC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EVC2 are known to be pathogenic (PMID: 17024374, 19810119, 19876929). This variant is present in population databases (rs750396637, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive Ellis-van Creveld syndrome (PMID: 19810119, 29068549). 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: 195541). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at