rs312480

Variant names:

• chr3-53495113-T-C
• rs312480
• NM_000720.4:c.-54T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, G2P
• complex neurodevelopmental disorder

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

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.-54T>C		5_prime_UTR	Exon 1 of 49	NP_000711.1	Q01668-2
	CACNA1D	NM_001128840.3	MANE Select	c.-54T>C		5_prime_UTR	Exon 1 of 48	NP_001122312.1	Q01668-1
	CACNA1D	NM_001128839.3		c.-54T>C		5_prime_UTR	Exon 1 of 46	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.-54T>C		5_prime_UTR	Exon 1 of 49	ENSP00000288139.3	Q01668-2
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.-54T>C		5_prime_UTR	Exon 1 of 48	ENSP00000288133.5	Q01668-1
	CACNA1D	ENST00000481478.2	TSL:1	c.-54T>C		5_prime_UTR	Exon 1 of 49	ENSP00000418014.2	H0Y879

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

African (AFR) AF: 0.661 AC: 18200 AN: 27538

American (AMR) AF: 0.940 AC: 40846 AN: 43434

Ashkenazi Jewish (ASJ) AF: 0.932 AC: 21763 AN: 23350

East Asian (EAS) AF: 0.974 AC: 35678 AN: 36640

South Asian (SAS) AF: 0.951 AC: 75931 AN: 79820

European-Finnish (FIN) AF: 0.929 AC: 45456 AN: 48954

Middle Eastern (MID) AF: 0.940 AC: 4674 AN: 4972

European-Non Finnish (NFE) AF: 0.896 AC: 746074 AN: 832714

Other (OTH) AF: 0.899 AC: 44069 AN: 49016

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

African (AFR) AF: 0.682 AC: 27072 AN: 39682

American (AMR) AF: 0.917 AC: 13728 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.931 AC: 3222 AN: 3460

East Asian (EAS) AF: 0.969 AC: 4744 AN: 4898

South Asian (SAS) AF: 0.948 AC: 4343 AN: 4582

European-Finnish (FIN) AF: 0.935 AC: 9365 AN: 10016

Middle Eastern (MID) AF: 0.959 AC: 280 AN: 292

European-Non Finnish (NFE) AF: 0.901 AC: 60775 AN: 67444

Other (OTH) AF: 0.882 AC: 1806 AN: 2048

Alfa AF: 0.885 Hom.: 72766

Bravo AF: 0.838

Asia WGS AF: 0.924 AC: 3208 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Aldosterone-producing adenoma with seizures and neurological abnormalities (1)
-	-	1	Sinoatrial node dysfunction and deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	20
DANN	Benign	0.80
PhyloP100		1.1
PromoterAI		-0.026	Neutral
Mutation Taster		=300/0	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: rs312480; hg19: chr3-53529140;