rs3774601

Variant names:

• chr3-53788866-G-A
• rs3774601
• NM_000720.4:c.4983+1914G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000720.4(CACNA1D):​c.4983+1914G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 152,020 control chromosomes in the GnomAD database, including 6,706 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6706 hom., cov: 32)
• Consequence: CACNA1D NM_000720.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• aldosterone-producing adenoma with seizures and neurological abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sinoatrial node dysfunction and deafness

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.4983+1914G>A		intron_variant	Intron 41 of 48	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.4923+1914G>A		intron_variant	Intron 40 of 47	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.4983+1914G>A		intron_variant	Intron 41 of 48	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.4923+1914G>A		intron_variant	Intron 40 of 47	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41331 AN: 151902 Hom.: 6707 Cov.: 32

Gnomad AFR AF: 0.0880

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.270

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.272 AC: 41334 AN: 152020 Hom.: 6706 Cov.: 32 AF XY: 0.270 AC XY: 20071 AN XY: 74306

African (AFR) AF: 0.0878 AC: 3641 AN: 41468

American (AMR) AF: 0.390 AC: 5948 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1369 AN: 3466

East Asian (EAS) AF: 0.232 AC: 1200 AN: 5178

South Asian (SAS) AF: 0.187 AC: 901 AN: 4818

European-Finnish (FIN) AF: 0.326 AC: 3445 AN: 10554

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23908 AN: 67954

Other (OTH) AF: 0.267 AC: 565 AN: 2114

Alfa AF: 0.333 Hom.: 15132

Bravo AF: 0.269

Asia WGS AF: 0.208 AC: 724 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.6
DANN	Benign	0.71
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3774601; hg19: chr3-53822893;