rs1045958

Positions:

chr3-53735452-C-T

Variant summary

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

The NM_000720.4(CACNA1D):c.2760C>T(p.Ser920=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,613,234 control chromosomes in the GnomAD database, including 84,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6327 hom., cov: 33)

Exomes 𝑓: 0.32 ( 78323 hom. )

Consequence

CACNA1D
NM_000720.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.01

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=-0.69).

BP6

Variant 3-53735452-C-T is Benign according to our data. Variant chr3-53735452-C-T is described in ClinVar as [Benign]. Clinvar id is 226470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53735452-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4 linkuse as main transcript	c.2760C>T	p.Ser920=	synonymous_variant	21/49	ENST00000288139.11
CACNA1D	NM_001128840.3 linkuse as main transcript	c.2700C>T	p.Ser900=	synonymous_variant	20/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11 linkuse as main transcript	c.2760C>T	p.Ser920=	synonymous_variant	21/49	1	NM_000720.4	P2	Q01668-2
CACNA1D	ENST00000350061.11 linkuse as main transcript	c.2700C>T	p.Ser900=	synonymous_variant	20/48	1	NM_001128840.3		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.259

AC:

39384

AN:

152078

Hom.:

6324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0658

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.373

Gnomad EAS

AF:

0.213

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.362

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.348

Gnomad OTH

AF:

0.273

GnomAD3 exomes

AF:

0.302

AC:

75995

AN:

251442

Hom.:

12488

AF XY:

0.303

AC XY:

41177

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0594

Gnomad AMR exome

AF:

0.322

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.217

Gnomad SAS exome

AF:

0.215

Gnomad FIN exome

AF:

0.369

Gnomad NFE exome

AF:

0.348

Gnomad OTH exome

AF:

0.325

GnomAD4 exome

AF:

0.322

AC:

471051

AN:

1461038

Hom.:

78323

Cov.:

AF XY:

0.321

AC XY:

233045

AN XY:

726902

show subpopulations

Gnomad4 AFR exome

AF:

0.0542

Gnomad4 AMR exome

AF:

0.319

Gnomad4 ASJ exome

AF:

0.368

Gnomad4 EAS exome

AF:

0.206

Gnomad4 SAS exome

AF:

0.213

Gnomad4 FIN exome

AF:

0.362

Gnomad4 NFE exome

AF:

0.341

Gnomad4 OTH exome

AF:

0.310

GnomAD4 genome

AF:

0.259

AC:

39398

AN:

152196

Hom.:

6327

Cov.:

AF XY:

0.259

AC XY:

19286

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0656

Gnomad4 AMR

AF:

0.302

Gnomad4 ASJ

AF:

0.373

Gnomad4 EAS

AF:

0.213

Gnomad4 SAS

AF:

0.219

Gnomad4 FIN

AF:

0.362

Gnomad4 NFE

AF:

0.348

Gnomad4 OTH

AF:

0.271

Alfa

AF:

0.312

Hom.:

5460

Bravo

AF:

0.245

Asia WGS

AF:

0.188

AC:

653

AN:

3478

EpiCase

AF:

0.327

EpiControl

AF:

0.333

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Ser920Ser in exon 21 of CACNA1D: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 34.9% (3003/8600) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1045958). -
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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Sinoatrial node dysfunction and deafness

Benign:2

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

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

-0.69

CADD

Benign

0.86

DANN

Benign

0.67

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

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