rs80359870
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001256789.3(CACNA1F):c.3133_3134insC(p.Leu1045ProfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,354 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001256789.3 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 |
---|---|---|---|---|---|---|---|
CACNA1F | NM_001256789.3 | c.3133_3134insC | p.Leu1045ProfsTer11 | frameshift_variant | 27/48 | ENST00000323022.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1F | ENST00000323022.10 | c.3133_3134insC | p.Leu1045ProfsTer11 | frameshift_variant | 27/48 | 1 | NM_001256789.3 | ||
CACNA1F | ENST00000376251.5 | c.2971_2972insC | p.Leu991ProfsTer11 | frameshift_variant | 27/48 | 1 | |||
CACNA1F | ENST00000376265.2 | c.3166_3167insC | p.Leu1056ProfsTer11 | frameshift_variant | 27/48 | 1 | P1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome AF: 9.16e-7 AC: 1AN: 1091354Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 357276
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2022 | 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; Common pathogenic variant among individuals of Dutch-German Mennonite background (Bech-Hansen et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); Also known as L991insC using alternate nomenclature; This variant is associated with the following publications: (PMID: 9662399, 28162000, 10900517, 18348259, 22744390, 33668843, 20301423, 9662400) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This sequence change creates a premature translational stop signal (p.Leu1056Profs*11) in the CACNA1F gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1F are known to be pathogenic (PMID: 9662399, 11281458, 17525176, 22194652, 24124559, 26992781). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked congenital stationary night blindness (PMID: 9662399, 9662400, 10900517). It is commonly reported in individuals of Mennonite ancestry (PMID: 9662399, 9662400, 10900517). This variant is also known as 3133inC, Leu991insC, and Leu1056insC. ClinVar contains an entry for this variant (Variation ID: 21443). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Congenital stationary night blindness 2A Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 08, 2022 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Apr 26, 2012 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 24, 2023 | Criteria applied: PVS1,PS4_MOD,PM2_SUP - |
CACNA1F-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 02, 2023 | The CACNA1F c.3166dupC variant is predicted to result in a frameshift and premature protein termination (p.Leu1056Profs*11). This variant has been reported in multiple individuals with congenital stationary night blindness (see for example Vincent and Héon et al. 2012. PubMed ID: 22744390; reported as c.3133insC in Strom et al. 1998. PubMed ID: 9662399). Frameshift variants in CACNA1F are expected to be pathogenic and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/21443). Given all the evidence, we interpret c.3166dup (p.Leu1056Profs*11) as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at