3-53495226-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000720.4(CACNA1D):c.60C>A(p.His20Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,754 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 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CACNA1D NM_000720.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1D
• BP4: Computational evidence support a benign effect (MetaRNN=0.12436232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.60C>A	p.His20Gln	missense_variant	1/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.60C>A	p.His20Gln	missense_variant	1/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.60C>A	p.His20Gln	missense_variant	1/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.60C>A	p.His20Gln	missense_variant	1/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152120 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248570 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461516 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74432

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 20 of the CACNA1D protein (p.His20Gln). This variant is present in population databases (rs201981216, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T;.;.;.;.;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.76	T;T;.;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.90	L;.;L;L;L;.;.
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D;.;.;D;N;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.023	D;.;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;.;.
Polyphen		0.69	P;.;B;B;.;.;.
Vest4		0.34
MutPred		0.25		Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);.;
MVP		0.84
MPC		0.80
ClinPred		0.66	D
GERP RS		3.2
Varity_R		0.23
gMVP		0.64

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: rs201981216; hg19: chr3-53529253;