3-53495227-G-A

Position:

chr3-53495227-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.19

Variant links:

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]

CACNA1D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.61G>A	p.Ala21Thr	missense_variant	1/49	ENST00000288139.11
CACNA1D	NM_001128840.3 linkuse as main transcript	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 linkuse as main transcript	c.61G>A	p.Ala21Thr	missense_variant	1/49	1	NM_000720.4	P2	Q01668-2
CACNA1D	ENST00000350061.11 linkuse as main transcript	c.61G>A	p.Ala21Thr	missense_variant	1/48	1	NM_001128840.3		Q01668-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248562

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134722

show subpopulations

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:

AN:

1461468

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727014

show subpopulations

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.;.;.;.;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

D;D;.;D;D;D;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.26

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Benign

0.90

L;.;L;L;L;.;.

MutationTaster

Benign

0.92

N;N;N

PrimateAI

Uncertain

0.69

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over