3-53495173-A-G

Variant names:

• chr3-53495173-A-G
• rs2090291645
• NM_000720.4:c.7A>G

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.7A>G​(p.Met3Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,176 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: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

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=0.20797089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.7A>G	p.Met3Val	missense_variant	Exon 1 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.7A>G	p.Met3Val	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.7A>G	p.Met3Val	missense_variant	Exon 1 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.7A>G	p.Met3Val	missense_variant	Exon 1 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151658 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460518 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726568

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151658 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74054

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 10, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T;.;.;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.0090
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.85	T;D;.;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.69	N;.;N;N;N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.47	N;.;.;N;N;.
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;.;.;D;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;.
Polyphen		0.0060	B;.;B;B;.;.
Vest4		0.60
MutPred		0.28		Gain of catalytic residue at M3 (P = 0.0012);Gain of catalytic residue at M3 (P = 0.0012);Gain of catalytic residue at M3 (P = 0.0012);Gain of catalytic residue at M3 (P = 0.0012);Gain of catalytic residue at M3 (P = 0.0012);Gain of catalytic residue at M3 (P = 0.0012);
MVP		0.97
MPC		0.81
ClinPred		0.41	T
GERP RS		4.1
Varity_R		0.85
gMVP		0.51

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: rs2090291645; hg19: chr3-53529200;