3-53762073-G-C

Position:

• chr3-53762073-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001128840.3(CACNA1D):​c.3862G>C​(p.Glu1288Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.38

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]

CACNA1D (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.3922G>C	p.Glu1308Gln	missense_variant	31/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.3862G>C	p.Glu1288Gln	missense_variant	30/48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.3922G>C	p.Glu1308Gln	missense_variant	31/49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.3862G>C	p.Glu1288Gln	missense_variant	30/48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;.;.;.;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	.;L;.;.;.;L;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	.;D;.;.;D;D;.;.
REVEL	Pathogenic	0.72
Sift	Benign	0.043	.;D;.;.;D;D;.;.
Sift4G	Uncertain	0.048	.;D;.;.;D;T;.;.
Polyphen		0.98, 1.0	.;D;.;D;D;.;.;.
Vest4		0.36, 0.34, 0.36
MutPred		0.62		.;Loss of catalytic residue at E1288 (P = 0.0979);Loss of catalytic residue at E1288 (P = 0.0979);.;.;Loss of catalytic residue at E1288 (P = 0.0979);Loss of catalytic residue at E1288 (P = 0.0979);.;
MVP		0.79
MPC		0.89
ClinPred		0.72	D
GERP RS		4.6
Varity_R		0.31
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs781171340; hg19: chr3-53796100;