chr3-53770462-C-T

Position:

• chr3-53770462-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000720.4(CACNA1D):​c.4014C>T​(p.Phe1338=) variant causes a synonymous change. The variant allele was found at a frequency of 0.031 in 1,613,542 control chromosomes in the GnomAD database, including 1,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (174 hom., cov: 33)
  • Exomes 𝑓: 0.030 (830 hom.)
• Consequence: CACNA1D NM_000720.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.00

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 3-53770462-C-T is Benign according to our data. Variant chr3-53770462-C-T is described in ClinVar as [Benign]. Clinvar id is 226475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53770462-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.4014C>T	p.Phe1338=	synonymous_variant	33/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.3954C>T	p.Phe1318=	synonymous_variant	32/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.4014C>T	p.Phe1338=	synonymous_variant	33/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.3954C>T	p.Phe1318=	synonymous_variant	32/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6284 AN: 152130 Hom.: 173 Cov.: 33

Gnomad AFR AF: 0.0720

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0431

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.00635

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.0631

GnomAD3 exomes AF: 0.0327 AC: 8222 AN: 251494 Hom.: 225 AF XY: 0.0331 AC XY: 4504 AN XY: 135922

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.0380

Gnomad ASJ exome AF: 0.0518

Gnomad EAS exome AF: 0.00767

Gnomad SAS exome AF: 0.0429

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.0298

Gnomad OTH exome AF: 0.0366

GnomAD4 exome AF: 0.0299 AC: 43727 AN: 1461294 Hom.: 830 Cov.: 31 AF XY: 0.0304 AC XY: 22127 AN XY: 726990

Gnomad4 AFR exome AF: 0.0772

Gnomad4 AMR exome AF: 0.0397

Gnomad4 ASJ exome AF: 0.0497

Gnomad4 EAS exome AF: 0.00494

Gnomad4 SAS exome AF: 0.0431

Gnomad4 FIN exome AF: 0.00534

Gnomad4 NFE exome AF: 0.0282

Gnomad4 OTH exome AF: 0.0346

GnomAD4 genome AF: 0.0414 AC: 6296 AN: 152248 Hom.: 174 Cov.: 33 AF XY: 0.0405 AC XY: 3016 AN XY: 74440

Gnomad4 AFR AF: 0.0720

Gnomad4 AMR AF: 0.0434

Gnomad4 ASJ AF: 0.0588

Gnomad4 EAS AF: 0.00656

Gnomad4 SAS AF: 0.0360

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.0295

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0349 Hom.: 255

Bravo AF: 0.0463

Asia WGS AF: 0.0260 AC: 91 AN: 3478

EpiCase AF: 0.0377

EpiControl AF: 0.0380

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Phe1338Phe in exon 33 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 7.1% (314/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17053501). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2019	- -
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	-0.30
CADD	Benign	13
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs17053501; hg19: chr3-53804489;