rs3774473

Variant names:

• chr3-53604824-G-A
• rs3774473
• NM_000720.4:c.484-45955G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-53604824-G-A
• chr3-53604824-G-T

Variant summary

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

The NM_000720.4(CACNA1D):​c.484-45955G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,148 control chromosomes in the GnomAD database, including 874 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 0.10 (874 hom., cov: 32)
• Consequence: CACNA1D NM_000720.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.491
• Publications: 11 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000720.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1D	NM_000720.4	MANE Plus Clinical	c.484-45955G>A		intron	N/A	NP_000711.1
	CACNA1D	NM_001128840.3	MANE Select	c.484-45955G>A		intron	N/A	NP_001122312.1
	CACNA1D	NM_001128839.3		c.484-45955G>A		intron	N/A	NP_001122311.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1D	ENST00000288139.11	TSL:1 MANE Plus Clinical	c.484-45955G>A		intron	N/A	ENSP00000288139.3
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.484-45955G>A		intron	N/A	ENSP00000288133.5
	CACNA1D	ENST00000481478.2	TSL:1	c.484-45955G>A		intron	N/A	ENSP00000418014.2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15908 AN: 152028 Hom.: 875 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0816

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0950

Gnomad OTH AF: 0.0981

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

GnomAD4 genome AF: 0.105 AC: 15914 AN: 152148 Hom.: 874 Cov.: 32 AF XY: 0.104 AC XY: 7762 AN XY: 74378

African (AFR) AF: 0.114 AC: 4734 AN: 41504

American (AMR) AF: 0.128 AC: 1947 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 149 AN: 3468

East Asian (EAS) AF: 0.175 AC: 905 AN: 5168

South Asian (SAS) AF: 0.114 AC: 548 AN: 4820

European-Finnish (FIN) AF: 0.0816 AC: 866 AN: 10614

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0950 AC: 6458 AN: 67986

Other (OTH) AF: 0.0956 AC: 202 AN: 2112

Alfa AF: 0.0984 Hom.: 2781

Bravo AF: 0.109

Asia WGS AF: 0.135 AC: 468 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.46
DANN	Benign	0.58
PhyloP100		-0.49
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: rs3774473; hg19: chr3-53638851;