chr3-53571818-C-T

Variant names:

• chr3-53571818-C-T
• rs10490772
• NM_000720.4:c.483+70098C>T

Variant summary

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

The NM_001128840.3(CACNA1D):​c.483+70098C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,194 control chromosomes in the GnomAD database, including 1,200 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 0.11 (1200 hom., cov: 32)
• Consequence: CACNA1D NM_001128840.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.741
• Publications: 9 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 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.483+70098C>T		intron	N/A	NP_000711.1	Q01668-2
	CACNA1D	NM_001128840.3	MANE Select	c.483+70098C>T		intron	N/A	NP_001122312.1	Q01668-1
	CACNA1D	NM_001128839.3		c.483+70098C>T		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.483+70098C>T		intron	N/A	ENSP00000288139.3	Q01668-2
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.483+70098C>T		intron	N/A	ENSP00000288133.5	Q01668-1
	CACNA1D	ENST00000481478.2	TSL:1	c.483+70098C>T		intron	N/A	ENSP00000418014.2	H0Y879

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16910 AN: 152076 Hom.: 1202 Cov.: 32

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.116

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

GnomAD4 genome AF: 0.111 AC: 16909 AN: 152194 Hom.: 1200 Cov.: 32 AF XY: 0.109 AC XY: 8145 AN XY: 74400

African (AFR) AF: 0.0328 AC: 1361 AN: 41534

American (AMR) AF: 0.123 AC: 1877 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 692 AN: 3468

East Asian (EAS) AF: 0.0150 AC: 78 AN: 5186

South Asian (SAS) AF: 0.123 AC: 593 AN: 4812

European-Finnish (FIN) AF: 0.105 AC: 1111 AN: 10598

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10662 AN: 67994

Other (OTH) AF: 0.114 AC: 241 AN: 2106

Alfa AF: 0.141 Hom.: 4927

Bravo AF: 0.109

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.4
DANN	Benign	0.56
PhyloP100		0.74
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: rs10490772; hg19: chr3-53605845;