rs147336902

chr3-53666373-G-Achr3-53666373-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000720.4(CACNA1D):c.954G>A(p.Ala318=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 1,614,136 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (39 hom.)
• Consequence: CACNA1D NM_000720.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.538

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 3-53666373-G-A is Benign according to our data. Variant chr3-53666373-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53666373-G-A is described in Lovd as [Benign]. Variant chr3-53666373-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.538 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00393 (599/152294) while in subpopulation NFE AF= 0.00637 (433/68020). AF 95% confidence interval is 0.00587. There are 4 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.954G>A	p.Ala318=	synonymous_variant	7/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.954G>A	p.Ala318=	synonymous_variant	7/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.954G>A	p.Ala318=	synonymous_variant	7/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.954G>A	p.Ala318=	synonymous_variant	7/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152176 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00637

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00412 AC: 1035 AN: 251416 Hom.: 6 AF XY: 0.00442 AC XY: 601 AN XY: 135874

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00617

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00571

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00524 AC: 7665 AN: 1461842 Hom.: 39 Cov.: 33 AF XY: 0.00536 AC XY: 3900 AN XY: 727230

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00674

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00588

Gnomad4 OTH exome AF: 0.00392

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152294 Hom.: 4 Cov.: 33 AF XY: 0.00367 AC XY: 273 AN XY: 74470

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00637

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00524 Hom.: 1

Bravo AF: 0.00347

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CACNA1D: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2019	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala318Ala 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 0.6% (52/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs147336902). -
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	-	- -

Aldosterone-producing adenoma with seizures and neurological abnormalities Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Sinoatrial node dysfunction and deafness;C3809609:Aldosterone-producing adenoma with seizures and neurological abnormalities Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 08, 2021

- -

CACNA1D-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	15
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147336902; hg19: chr3-53700400;