NM_000720.4:c.483+2132T>C

Variant names:

• chr3-53503852-T-C
• rs6763768
• NM_000720.4:c.483+2132T>C

Variant summary

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

The NM_000720.4(CACNA1D):​c.483+2132T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 151,704 control chromosomes in the GnomAD database, including 8,843 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 0.34 (8843 hom., cov: 30)
• Consequence: CACNA1D NM_000720.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 16 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.483+2132T>C		intron_variant	Intron 3 of 48	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.483+2132T>C		intron_variant	Intron 3 of 47	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.483+2132T>C		intron_variant	Intron 3 of 48	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.483+2132T>C		intron_variant	Intron 3 of 47	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50830 AN: 151586 Hom.: 8830 Cov.: 30

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.348

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

GnomAD4 genome AF: 0.335 AC: 50864 AN: 151704 Hom.: 8843 Cov.: 30 AF XY: 0.336 AC XY: 24939 AN XY: 74116

African (AFR) AF: 0.263 AC: 10872 AN: 41356

American (AMR) AF: 0.428 AC: 6534 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1136 AN: 3466

East Asian (EAS) AF: 0.351 AC: 1799 AN: 5130

South Asian (SAS) AF: 0.261 AC: 1249 AN: 4788

European-Finnish (FIN) AF: 0.380 AC: 3995 AN: 10512

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.353 AC: 23939 AN: 67892

Other (OTH) AF: 0.350 AC: 736 AN: 2104

Alfa AF: 0.350 Hom.: 42365

Bravo AF: 0.341

Asia WGS AF: 0.300 AC: 1048 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	9.1
DANN	Benign	0.66
PhyloP100		0.058
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: rs6763768; hg19: chr3-53537879;