rs763363403
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_147127.5(EVC2):c.942G>A(p.Trp314Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,048 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_147127.5 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 | UniProt |
---|---|---|---|---|---|---|---|
EVC2 | NM_147127.5 | c.942G>A | p.Trp314Ter | stop_gained | 8/22 | ENST00000344408.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC2 | ENST00000344408.10 | c.942G>A | p.Trp314Ter | stop_gained | 8/22 | 1 | NM_147127.5 | P2 | |
EVC2 | ENST00000310917.6 | c.702G>A | p.Trp234Ter | stop_gained | 8/22 | 1 | A2 | ||
EVC2 | ENST00000475313.5 | c.702G>A | p.Trp234Ter | stop_gained, NMD_transcript_variant | 8/23 | 1 | |||
EVC2 | ENST00000509670.1 | c.702G>A | p.Trp234Ter | stop_gained, NMD_transcript_variant | 9/23 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251468Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727242
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
Ellis-van Creveld syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained variant has been reported previously in homozygous state in a family affected with Ellis-van Creveld syndrome (Aziz A. et al., 2016). The p.Trp314Ter variant is reported with the allele frequency (0.0008%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. No significant reportable EVC2 variant was detected in the spouse. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 06, 2017 | - - |
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This sequence change creates a premature translational stop signal (p.Trp314*) 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 (rs763363403, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Ellis-van Creveld syndrome (PMID: 26580685). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Trp234*. ClinVar contains an entry for this variant (Variation ID: 550977). For these reasons, this variant has been classified as Pathogenic. - |
EVC2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 15, 2022 | The EVC2 c.942G>A variant is predicted to result in premature protein termination (p.Trp314*). This variant has been reported in the homozygous state in at least two individuals with Ellis-van Creveld syndrome (Aziz et al 2016. PubMed ID: 26580685; Eftekhariyazdi et al 2020. PubMed ID: 32072716). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-5667305-C-T). Nonsense variants in EVC2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at