rs770886605
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_000720.4(CACNA1D):c.5873C>T(p.Pro1958Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,609,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1958P) has been classified as Likely benign.
Frequency
Consequence
NM_000720.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1D | NM_000720.4 | c.5873C>T | p.Pro1958Leu | missense_variant | 47/49 | ENST00000288139.11 | |
CACNA1D | NM_001128840.3 | c.5813C>T | p.Pro1938Leu | missense_variant | 46/48 | ENST00000350061.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1D | ENST00000288139.11 | c.5873C>T | p.Pro1958Leu | missense_variant | 47/49 | 1 | NM_000720.4 | P2 | |
CACNA1D | ENST00000350061.11 | c.5813C>T | p.Pro1938Leu | missense_variant | 46/48 | 1 | NM_001128840.3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000444 AC: 11AN: 247672Hom.: 0 AF XY: 0.0000298 AC XY: 4AN XY: 134276
GnomAD4 exome AF: 0.0000275 AC: 40AN: 1456992Hom.: 0 Cov.: 31 AF XY: 0.0000221 AC XY: 16AN XY: 725040
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 24, 2023 | BP4, PP2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1958 of the CACNA1D protein (p.Pro1958Leu). This variant is present in population databases (rs770886605, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. ClinVar contains an entry for this variant (Variation ID: 505106). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 06, 2020 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 20, 2016 | p.Pro1958Leu in exon 47 of CACNA1D: This variant is not expected to have clinica l significance due to a lack of conservation across species, including mammals. Of note, 8 mammals have a leucine (Leu) at this position despite high nearby ami no acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. This variant has been identified in 1/8586 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs770886605). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 07, 2020 | DNA sequence analysis of the CACNA1D gene demonstrated a sequence change, c.5873C>T, in exon 47 that results in an amino acid change, p.Pro1958Leu. This sequence change does not appear to have been previously described in patients with CACNA1D-related disorders and has has been described in the gnomAD database with a low population frequency of 0.0044% (dbSNP rs770886605). The p.Pro1958Leu change affects a moderately conserved amino acid residue located in a domain of the CACNA1D protein that is not known to be functional. The p.Pro1958Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at