rs1553659646

Positions:

• chr3-53747388-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001128840.3(CACNA1D):​c.3254A>G​(p.Asp1085Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31

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 Likely_pathogenic. Variant got 7 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). 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.3314A>G	p.Asp1105Gly	missense_variant	27/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.3254A>G	p.Asp1085Gly	missense_variant	26/48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.3314A>G	p.Asp1105Gly	missense_variant	27/49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.3254A>G	p.Asp1085Gly	missense_variant	26/48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	.;M;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.6	.;D;.;.;D;D;.;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;D;.;.;D;D;.;.;D
Sift4G	Uncertain	0.0020	.;D;.;.;D;D;.;.;D
Polyphen		1.0, 0.95	.;D;.;D;D;.;.;.;P
Vest4		0.97, 0.97, 0.98
MutPred		0.82		.;Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);.;.;Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);.;.;
MVP		1.0
MPC		2.2
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.89
gMVP		0.98

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: rs1553659646; hg19: chr3-53781415;