chr4-5622775-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_147127.5(EVC2):c.2263C>T(p.Gln755Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000291 in 1,613,918 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q755Q) has been classified as Likely benign. 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.2263C>T | p.Gln755Ter | stop_gained | 14/22 | ENST00000344408.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC2 | ENST00000344408.10 | c.2263C>T | p.Gln755Ter | stop_gained | 14/22 | 1 | NM_147127.5 | P2 | |
EVC2 | ENST00000310917.6 | c.2023C>T | p.Gln675Ter | stop_gained | 14/22 | 1 | A2 | ||
EVC2 | ENST00000475313.5 | c.2023C>T | p.Gln675Ter | stop_gained, NMD_transcript_variant | 14/23 | 1 | |||
EVC2 | ENST00000509670.1 | c.*656C>T | 3_prime_UTR_variant, NMD_transcript_variant | 15/23 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251264Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135830
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727220
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74276
ClinVar
Submissions by phenotype
Ellis-van Creveld syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 11, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 18, 2024 | Variant summary: EVC2 c.2263C>T (p.Gln755X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251264 control chromosomes. c.2263C>T has been reported in the literature in at least one compound heterozygous individual affected with Ellis-van Creveld syndrome (e.g. Tompson_2007). 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: 194442). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | This sequence change creates a premature translational stop signal (p.Gln755*) 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 (rs751356206, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Ellis van-Creveld syndrome (PMID: 17024374). ClinVar contains an entry for this variant (Variation ID: 194442). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 03, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Hereditary insensitivity to pain with anhidrosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 18, 2024 | Variant summary: NTRK1 c.2263C>T (p.Arg755Trp) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 227242 control chromosomes. c.2263C>T has been reported in the literature in multiple individuals affected with Hereditary Insensitivity To Pain With Anhidrosis. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 18, 2024 | Variant summary: LZTR1 c.2263C>T (p.Arg755Trp) results in a non-conservative amino acid change located in the BTB/POZ domain (IPR000210) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2263C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at