rs2250736

chr3-53666523-T-Cchr3-53666523-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000720.4(CACNA1D):c.1104T>C(p.Asp368=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 1,612,480 control chromosomes in the GnomAD database, including 260,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33235 hom., cov: 32)
  • Exomes 𝑓: 0.55 (226847 hom.)
• Consequence: CACNA1D NM_000720.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.98

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-53666523-T-C is Benign according to our data. Variant chr3-53666523-T-C is described in ClinVar as [Benign]. Clinvar id is 226467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53666523-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.98 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.1104T>C	p.Asp368=	synonymous_variant	7/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.1104T>C	p.Asp368=	synonymous_variant	7/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.1104T>C	p.Asp368=	synonymous_variant	7/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.1104T>C	p.Asp368=	synonymous_variant	7/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97722 AN: 151976 Hom.: 33179 Cov.: 32

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.586

GnomAD3 exomes AF: 0.588 AC: 147643 AN: 250970 Hom.: 44701 AF XY: 0.583 AC XY: 79065 AN XY: 135622

Gnomad AFR exome AF: 0.888

Gnomad AMR exome AF: 0.598

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.618

Gnomad SAS exome AF: 0.660

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.526

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.553 AC: 807057 AN: 1460384 Hom.: 226847 Cov.: 38 AF XY: 0.554 AC XY: 402673 AN XY: 726622

Gnomad4 AFR exome AF: 0.893

Gnomad4 AMR exome AF: 0.596

Gnomad4 ASJ exome AF: 0.479

Gnomad4 EAS exome AF: 0.666

Gnomad4 SAS exome AF: 0.652

Gnomad4 FIN exome AF: 0.592

Gnomad4 NFE exome AF: 0.528

Gnomad4 OTH exome AF: 0.568

GnomAD4 genome AF: 0.643 AC: 97838 AN: 152096 Hom.: 33235 Cov.: 32 AF XY: 0.646 AC XY: 48021 AN XY: 74372

Gnomad4 AFR AF: 0.875

Gnomad4 AMR AF: 0.587

Gnomad4 ASJ AF: 0.485

Gnomad4 EAS AF: 0.636

Gnomad4 SAS AF: 0.664

Gnomad4 FIN AF: 0.596

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.582

Alfa AF: 0.552 Hom.: 31496

Bravo AF: 0.651

Asia WGS AF: 0.680 AC: 2364 AN: 3478

EpiCase AF: 0.526

EpiControl AF: 0.514

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asp368Asp in exon 7 of CACNA1D: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 46.7% (4012/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2250736). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Aldosterone-producing adenoma with seizures and neurological abnormalities Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Sinoatrial node dysfunction and deafness Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.2
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2250736; hg19: chr3-53700550; COSMIC: COSV55450266;