rs138150805
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP2PP3
The ENST00000350061.11(CACNA1D):c.1555G>A(p.Ala519Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000681 in 1,614,088 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A519A) has been classified as Likely benign.
Frequency
Consequence
ENST00000350061.11 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1D | NM_000720.4 | c.1615G>A | p.Ala539Thr | missense_variant | 13/49 | ENST00000288139.11 | NP_000711.1 | |
CACNA1D | NM_001128840.3 | c.1555G>A | p.Ala519Thr | missense_variant | 12/48 | ENST00000350061.11 | NP_001122312.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1D | ENST00000288139.11 | c.1615G>A | p.Ala539Thr | missense_variant | 13/49 | 1 | NM_000720.4 | ENSP00000288139 | P2 | |
CACNA1D | ENST00000350061.11 | c.1555G>A | p.Ala519Thr | missense_variant | 12/48 | 1 | NM_001128840.3 | ENSP00000288133 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251494Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135922
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727242
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 11, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 539 of the CACNA1D protein (p.Ala539Thr). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1D protein function. ClinVar contains an entry for this variant (Variation ID: 504804). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. This variant is present in population databases (rs138150805, gnomAD 0.004%). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 06, 2016 | The p.Ala539Thr variant in CACNA1D has not been previously reported in individua ls with hearing loss, but has been identified in 1/11576 Latino chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 38150805). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. In summary, the clini cal significance of the p.Ala539Thr variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at