3-53495206-C-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_001128840.3(CACNA1D):c.40C>T(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
CACNA1D
NM_001128840.3 missense
NM_001128840.3 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 0.848
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 Likely_benign. Variant got -1 ACMG points.
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). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 27 curated benign missense variants. GenCC has associacion of the gene with sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
BP4
Computational evidence support a benign effect (MetaRNN=0.254406).
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1D | ENST00000288139.11 | c.40C>T | p.Arg14Trp | missense_variant | 1/49 | 1 | NM_000720.4 | ENSP00000288139.3 | ||
CACNA1D | ENST00000350061.11 | c.40C>T | p.Arg14Trp | missense_variant | 1/48 | 1 | NM_001128840.3 | ENSP00000288133.5 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152078Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248674Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134760
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GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461058Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 726818
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152078Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74302
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 13, 2023 | This variant is present in population databases (rs766424529, gnomAD 0.008%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 14 of the CACNA1D protein (p.Arg14Trp). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;L;L;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N;N;.;.
REVEL
Uncertain
Sift
Pathogenic
D;.;.;D;D;.;.
Sift4G
Uncertain
D;.;.;D;D;.;.
Polyphen
D;.;D;D;.;.;.
Vest4
MVP
MPC
0.86
ClinPred
T
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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