rs36061665

chr3-53747413-G-Achr3-53747413-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000720.4(CACNA1D):c.3339G>A(p.Ala1113=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,614,168 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1113A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (8 hom.)
• Consequence: CACNA1D NM_000720.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.90

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-53747413-G-A is Benign according to our data. Variant chr3-53747413-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53747413-G-A is described in Lovd as [Benign]. Variant chr3-53747413-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00251 (383/152352) while in subpopulation NFE AF= 0.004 (272/68030). AF 95% confidence interval is 0.00361. There are 1 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.3339G>A	p.Ala1113=	synonymous_variant	27/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.3279G>A	p.Ala1093=	synonymous_variant	26/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.3339G>A	p.Ala1113=	synonymous_variant	27/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.3279G>A	p.Ala1093=	synonymous_variant	26/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 383 AN: 152234 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00203 AC: 510 AN: 251456 Hom.: 0 AF XY: 0.00206 AC XY: 280 AN XY: 135902

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00313

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00350 AC: 5118 AN: 1461816 Hom.: 8 Cov.: 32 AF XY: 0.00340 AC XY: 2469 AN XY: 727210

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00419

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.00251 AC: 383 AN: 152352 Hom.: 1 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74504

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00400

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000643 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CACNA1D: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2018	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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala1113Ala in exon 27 of CACNA1D: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.4% (33/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs36061665). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.16
Dann	Benign	0.66

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: rs36061665; hg19: chr3-53781440; COSMIC: COSV55448181; COSMIC: COSV55448181;