3-53675824-T-C

Variant names:

• chr3-53675824-T-C
• rs1460118
• NM_000720.4:c.1220+2008T>C

Variant summary

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

The NM_001128840.3(CACNA1D):​c.1220+2698T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 152,018 control chromosomes in the GnomAD database, including 7,922 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 0.32 (7922 hom., cov: 32)
• Consequence: CACNA1D NM_001128840.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• 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, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• sinoatrial node dysfunction and deafness

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128840.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1D	NM_000720.4	MANE Plus Clinical	c.1220+2008T>C		intron	N/A	NP_000711.1	Q01668-2
	CACNA1D	NM_001128840.3	MANE Select	c.1220+2698T>C		intron	N/A	NP_001122312.1	Q01668-1
	CACNA1D	NM_001128839.3		c.1220+2698T>C		intron	N/A	NP_001122311.1	Q01668-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1D	ENST00000288139.11	TSL:1 MANE Plus Clinical	c.1220+2008T>C		intron	N/A	ENSP00000288139.3	Q01668-2
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.1220+2698T>C		intron	N/A	ENSP00000288133.5	Q01668-1
	CACNA1D	ENST00000481478.2	TSL:1	c.1220+2698T>C		intron	N/A	ENSP00000418014.2	H0Y879

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49289 AN: 151900 Hom.: 7911 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.323

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

GnomAD4 genome AF: 0.325 AC: 49332 AN: 152018 Hom.: 7922 Cov.: 32 AF XY: 0.323 AC XY: 23990 AN XY: 74336

African (AFR) AF: 0.336 AC: 13911 AN: 41454

American (AMR) AF: 0.323 AC: 4941 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1044 AN: 3468

East Asian (EAS) AF: 0.276 AC: 1426 AN: 5174

South Asian (SAS) AF: 0.220 AC: 1059 AN: 4820

European-Finnish (FIN) AF: 0.306 AC: 3235 AN: 10572

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22605 AN: 67944

Other (OTH) AF: 0.327 AC: 687 AN: 2104

Alfa AF: 0.326 Hom.: 25837

Bravo AF: 0.324

Asia WGS AF: 0.255 AC: 889 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		1.5
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: rs1460118; hg19: chr3-53709851;