rs2250736

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001128840.3(CACNA1D):c.1104T>C(p.Asp368Asp) 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_001128840.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.98

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 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 rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4 link	c.1104T>C	p.Asp368Asp	synonymous_variant	Exon 7 of 49	ENST00000288139.11	NP_000711.1	Q01668-2Q59GD8
CACNA1D	NM_001128840.3 link	c.1104T>C	p.Asp368Asp	synonymous_variant	Exon 7 of 48	ENST00000350061.11	NP_001122312.1	Q01668-1Q59GD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11 link	c.1104T>C	p.Asp368Asp	synonymous_variant	Exon 7 of 49	1	NM_000720.4	ENSP00000288139.3		Q01668-2
CACNA1D	ENST00000350061.11 link	c.1104T>C	p.Asp368Asp	synonymous_variant	Exon 7 of 48	1	NM_001128840.3	ENSP00000288133.5		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.643

AC:

97722

AN:

151976

Hom.:

33179

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.554

AC XY:

402673

AN XY:

726622

show subpopulations

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.:

AF XY:

0.646

AC XY:

48021

AN XY:

74372

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aldosterone-producing adenoma with seizures and neurological abnormalities

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sinoatrial node dysfunction and deafness

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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