rs992326794
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_147127.5(EVC2):c.198_199insGGCGG(p.Ser67GlyfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R66R) 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.198_199insGGCGG | p.Ser67GlyfsTer17 | frameshift_variant | 1/22 | ENST00000344408.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC2 | ENST00000344408.10 | c.198_199insGGCGG | p.Ser67GlyfsTer17 | frameshift_variant | 1/22 | 1 | NM_147127.5 | P2 | |
EVC2 | ENST00000310917.6 | c.-13+513_-13+514insGGCGG | intron_variant | 1 | A2 | ||||
EVC2 | ENST00000475313.5 | c.-13+513_-13+514insGGCGG | intron_variant, NMD_transcript_variant | 1 | |||||
EVC2 | ENST00000509670.1 | c.-106-176_-106-175insGGCGG | intron_variant, NMD_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000667 AC: 1AN: 149994Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000305 AC: 4AN: 1309508Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 642438
GnomAD4 genome ? AF: 0.00000667 AC: 1AN: 149994Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73228
ClinVar
Submissions by phenotype
Ellis-van Creveld syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2003 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 25, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 11, 2024 | Variant summary: EVC2 c.194_198dupGGCGG (p.Ser67GlyfsX17) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 31290 control chromosomes (gnomAD). c.194_198dupGGCGG has been reported in the literature as a biallelic genotype in at least one individual affected with Ellis-van Creveld syndrome (e.g. Tompson_2007). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 17024374). ClinVar contains an entry for this variant (Variation ID: 556341). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change creates a premature translational stop signal (p.Ser67Glyfs*17) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with EVC2-related conditions (PMID: 12571802). This variant is also known as c.198insGGCGG. ClinVar contains an entry for this variant (Variation ID: 556341). 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