3-53495207-G-A

Variant names:

• chr3-53495207-G-A
• rs776581643
• NM_000720.4:c.41G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001128840.3(CACNA1D):​c.41G>A​(p.Arg14Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,296 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: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1D gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 27 curated benign missense variants. Gene score misZ: 4.5817 (above the threshold of 3.09). Trascript score misZ: 6.6073 (above the threshold of 3.09). GenCC associations: The gene is linked to sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18624839).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.41G>A	p.Arg14Gln	missense_variant	Exon 1 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.41G>A	p.Arg14Gln	missense_variant	Exon 1 of 48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.41G>A	p.Arg14Gln	missense_variant	Exon 1 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.41G>A	p.Arg14Gln	missense_variant	Exon 1 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248688 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461296 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 14 of the CACNA1D protein (p.Arg14Gln). This variant is present in population databases (rs776581643, gnomAD 0.0009%). 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: 1493473). 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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;.;.;.;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.55	N;.;N;N;N;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.55	N;.;.;N;N;.;.
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;.;.;D;D;.;.
Sift4G	Benign	0.23	T;.;.;T;T;.;.
Polyphen		0.11	B;.;B;B;.;.;.
Vest4		0.34
MutPred		0.33		Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;
MVP		0.74
MPC		0.92
ClinPred		0.57	D
GERP RS		3.8
Varity_R		0.29
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776581643; hg19: chr3-53529234;