chr3-53495227-G-A

Position:

• chr3-53495227-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000720.4(CACNA1D):​c.61G>A​(p.Ala21Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,468 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1D NM_000720.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19

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 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 6.6047 (greater than threshold 3.09). GenCC has associacion of gene with sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25853488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.61G>A	p.Ala21Thr	missense_variant	1/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.61G>A	p.Ala21Thr	missense_variant	1/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.61G>A	p.Ala21Thr	missense_variant	1/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.61G>A	p.Ala21Thr	missense_variant	1/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248562 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134722

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461468 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

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.: 31

Bravo AF: 0.00000378

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

Jun 16, 2024

The c.61G>A (p.A21T) alteration is located in exon 1 (coding exon 1) of the CACNA1D gene. This alteration results from a G to A substitution at nucleotide position 61, causing the alanine (A) at amino acid position 21 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;.;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.90	L;.;L;L;L;.;.
MutationTaster	Benign	0.92	N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N;.;.;N;N;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.12	T;.;.;T;T;.;.
Sift4G	Uncertain	0.023	D;.;.;D;D;.;.
Polyphen		0.96	D;.;P;P;.;.;.
Vest4		0.26
MutPred		0.20		Gain of glycosylation at Y26 (P = 0.0019);Gain of glycosylation at Y26 (P = 0.0019);Gain of glycosylation at Y26 (P = 0.0019);Gain of glycosylation at Y26 (P = 0.0019);Gain of glycosylation at Y26 (P = 0.0019);Gain of glycosylation at Y26 (P = 0.0019);.;
MVP		0.81
MPC		0.78
ClinPred		0.38	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.36

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: rs1461864281; hg19: chr3-53529254;