rs138150805
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP2PP3
The NM_001128840.3(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 (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
CACNA1D
NM_001128840.3 missense
NM_001128840.3 missense
Scores
7
7
5
Clinical Significance
Conservation
PhyloP100: 6.96
Genes affected
CACNA1D (HGNC:1391): (calcium voltage-gated channel subunit alpha1 D) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a repeat II (size 246) in uniprot entity CAC1D_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001128840.3
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1D. . Gene score misZ 4.5817 (greater than the threshold 3.09). Trascript score misZ 6.6073 (greater than threshold 3.09). GenCC has associacion of gene with sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.779
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 | ENSP00000288139.3 | ||
CACNA1D | ENST00000350061.11 | c.1555G>A | p.Ala519Thr | missense_variant | 12/48 | 1 | NM_001128840.3 | ENSP00000288133.5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251494Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135922
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727242
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74356
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;T;.;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;M;.;.;.;M;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D;.;.;D;D;.;.;D
REVEL
Uncertain
Sift
Benign
.;T;.;.;T;T;.;.;T
Sift4G
Benign
.;T;.;.;T;T;.;.;T
Polyphen
0.95, 1.0, 0.98
.;P;.;D;D;.;.;.;D
Vest4
0.50, 0.51, 0.50
MVP
0.83
MPC
1.5
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at