rs34388124

Positions:

chr3-53810157-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000720.4(CACNA1D):c.6111G>A(p.Pro2037=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,613,936 control chromosomes in the GnomAD database, including 1,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 89 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1008 hom. )

Consequence

CACNA1D
NM_000720.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -5.01

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=-0.72).

BP6

Variant 3-53810157-G-A is Benign according to our data. Variant chr3-53810157-G-A is described in ClinVar as [Benign]. Clinvar id is 226477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53810157-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.01 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0265 (4041/152294) while in subpopulation NFE AF= 0.0374 (2542/68012). AF 95% confidence interval is 0.0362. There are 89 homozygotes in gnomad4. There are 1930 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 89 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4 linkuse as main transcript	c.6111G>A	p.Pro2037=	synonymous_variant	48/49	ENST00000288139.11
CACNA1D	NM_001128840.3 linkuse as main transcript	c.6051G>A	p.Pro2017=	synonymous_variant	47/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11 linkuse as main transcript	c.6111G>A	p.Pro2037=	synonymous_variant	48/49	1	NM_000720.4	P2	Q01668-2
CACNA1D	ENST00000350061.11 linkuse as main transcript	c.6051G>A	p.Pro2017=	synonymous_variant	47/48	1	NM_001128840.3		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4040

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00637

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0244

Gnomad ASJ

AF:

0.0518

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0246

Gnomad FIN

AF:

0.0436

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0374

Gnomad OTH

AF:

0.0292

GnomAD3 exomes

AF:

0.0303

AC:

7617

AN:

251262

Hom.:

153

AF XY:

0.0316

AC XY:

4288

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00585

Gnomad AMR exome

AF:

0.0179

Gnomad ASJ exome

AF:

0.0522

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0245

Gnomad FIN exome

AF:

0.0419

Gnomad NFE exome

AF:

0.0397

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0349

AC:

51057

AN:

1461642

Hom.:

1008

Cov.:

AF XY:

0.0349

AC XY:

25356

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00499

Gnomad4 AMR exome

AF:

0.0187

Gnomad4 ASJ exome

AF:

0.0533

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0237

Gnomad4 FIN exome

AF:

0.0399

Gnomad4 NFE exome

AF:

0.0380

Gnomad4 OTH exome

AF:

0.0323

GnomAD4 genome

AF:

0.0265

AC:

4041

AN:

152294

Hom.:

Cov.:

AF XY:

0.0259

AC XY:

1930

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00638

Gnomad4 AMR

AF:

0.0244

Gnomad4 ASJ

AF:

0.0518

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0251

Gnomad4 FIN

AF:

0.0436

Gnomad4 NFE

AF:

0.0374

Gnomad4 OTH

AF:

0.0289

Alfa

AF:

0.0348

Hom.:

Bravo

AF:

0.0251

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0396

EpiControl

AF:

0.0406

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro2037Pro in exon 48 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 3.9% (332/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34388124). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.33

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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