3-53666523-T-G

Variant names:

• chr3-53666523-T-G
• NM_000720.4:c.1104T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_001128840.3(CACNA1D):​c.1104T>G​(p.Asp368Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D368D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a repeat I (size 296) in uniprot entity CAC1D_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001128840.3
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.1104T>G	p.Asp368Glu	missense_variant	Exon 7 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.1104T>G	p.Asp368Glu	missense_variant	Exon 7 of 48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.1104T>G	p.Asp368Glu	missense_variant	Exon 7 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.1104T>G	p.Asp368Glu	missense_variant	Exon 7 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.80	.;D;.;.;.;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.86	D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.0	.;L;.;L;L;L;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.4	.;D;.;.;D;D;.;.;D
REVEL	Uncertain	0.64
Sift	Benign	0.072	.;T;.;.;T;T;.;.;T
Sift4G	Benign	0.11	.;T;.;.;T;T;.;.;T
Polyphen		0.76, 1.0, 0.91	.;P;.;D;D;.;.;.;P
Vest4		0.60, 0.40, 0.59
MutPred		0.67		.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;
MVP		0.95
MPC		1.8
ClinPred		0.94	D
GERP RS		-7.7
Varity_R		0.31
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-53700550;