rs312480

Positions:

• chr3-53495113-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001128840.3(CACNA1D):​c.-54T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 1,294,732 control chromosomes in the GnomAD database, including 520,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (54273 hom., cov: 22)
  • Exomes 𝑓: 0.90 (466366 hom.)
• Consequence: CACNA1D NM_001128840.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.06

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 3-53495113-T-C is Benign according to our data. Variant chr3-53495113-T-C is described in ClinVar as [Benign]. Clinvar id is 1192642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.-54T>C		5_prime_UTR_variant	1/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.-54T>C		5_prime_UTR_variant	1/48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139	c.-54T>C		5_prime_UTR_variant	1/49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061	c.-54T>C		5_prime_UTR_variant	1/48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.851 AC: 126082 AN: 148186 Hom.: 54242 Cov.: 22

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.917

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.948

Gnomad FIN AF: 0.935

Gnomad MID AF: 0.955

Gnomad NFE AF: 0.901

Gnomad OTH AF: 0.882

GnomAD4 exome AF: 0.901 AC: 1032691 AN: 1146438 Hom.: 466366 Cov.: 15 AF XY: 0.904 AC XY: 527739 AN XY: 584020

Gnomad4 AFR exome AF: 0.661

Gnomad4 AMR exome AF: 0.940

Gnomad4 ASJ exome AF: 0.932

Gnomad4 EAS exome AF: 0.974

Gnomad4 SAS exome AF: 0.951

Gnomad4 FIN exome AF: 0.929

Gnomad4 NFE exome AF: 0.896

Gnomad4 OTH exome AF: 0.899

GnomAD4 genome AF: 0.851 AC: 126164 AN: 148294 Hom.: 54273 Cov.: 22 AF XY: 0.856 AC XY: 61813 AN XY: 72248

Gnomad4 AFR AF: 0.682

Gnomad4 AMR AF: 0.917

Gnomad4 ASJ AF: 0.931

Gnomad4 EAS AF: 0.969

Gnomad4 SAS AF: 0.948

Gnomad4 FIN AF: 0.935

Gnomad4 NFE AF: 0.901

Gnomad4 OTH AF: 0.882

Alfa AF: 0.892 Hom.: 57266

Bravo AF: 0.838

Asia WGS AF: 0.924 AC: 3208 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -

Aldosterone-producing adenoma with seizures and neurological abnormalities Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Sinoatrial node dysfunction and deafness Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	20
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs312480; hg19: chr3-53529140;