3-53798876-T-G

Variant names:

• chr3-53798876-T-G
• rs3774609
• NM_000720.4:c.4984-1373T>G

Variant summary

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

The NM_000720.4(CACNA1D):​c.4984-1373T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 152,022 control chromosomes in the GnomAD database, including 22,523 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 0.51 (22523 hom., cov: 32)
• Consequence: CACNA1D NM_000720.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.541
• Publications: 13 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.4984-1373T>G		intron_variant	Intron 41 of 48	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.4924-1373T>G		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.4984-1373T>G		intron_variant	Intron 41 of 48	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.4924-1373T>G		intron_variant	Intron 40 of 47	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77557 AN: 151904 Hom.: 22470 Cov.: 32

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.511 AC: 77674 AN: 152022 Hom.: 22523 Cov.: 32 AF XY: 0.503 AC XY: 37386 AN XY: 74326

African (AFR) AF: 0.803 AC: 33295 AN: 41474

American (AMR) AF: 0.520 AC: 7944 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1747 AN: 3472

East Asian (EAS) AF: 0.382 AC: 1968 AN: 5158

South Asian (SAS) AF: 0.267 AC: 1283 AN: 4810

European-Finnish (FIN) AF: 0.343 AC: 3621 AN: 10570

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.388 AC: 26376 AN: 67940

Other (OTH) AF: 0.475 AC: 1001 AN: 2108

Alfa AF: 0.390 Hom.: 6460

Bravo AF: 0.540

Asia WGS AF: 0.368 AC: 1280 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.9
DANN	Benign	0.76
PhyloP100		-0.54
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: rs3774609; hg19: chr3-53832903;