chr3-53723517-G-C

Variant names:

• chr3-53723517-G-C
• NM_000720.4:c.1810G>C

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.1750G>C​(p.Val584Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.15

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 II (size 246) in uniprot entity CAC1D_HUMAN there are 4 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, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.1810G>C	p.Val604Leu	missense_variant	Exon 14 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.1750G>C	p.Val584Leu	missense_variant	Exon 13 of 48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.1810G>C	p.Val604Leu	missense_variant	Exon 14 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.1750G>C	p.Val584Leu	missense_variant	Exon 13 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	.;L;.;.;.;L;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.3	.;N;.;.;N;N;.;.;N
REVEL	Pathogenic	0.70
Sift	Benign	0.034	.;D;.;.;D;D;.;.;D
Sift4G	Benign	0.29	.;T;.;.;T;T;.;.;T
Polyphen		0.96, 0.10, 0.40	.;D;.;B;B;.;.;.;B
Vest4		0.61, 0.63, 0.60
MutPred		0.57		.;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		0.93
MPC		1.9
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.43
gMVP		0.79

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: chr3-53757544;