rs147336902

Variant names:

• chr3-53666373-G-A
• rs147336902
• NM_000720.4:c.954G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-53666373-G-A
• chr3-53666373-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001128840.3(CACNA1D):​c.954G>A​(p.Ala318Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 1,614,136 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (39 hom.)
• Consequence: CACNA1D NM_001128840.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.538
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.133).
• BP6: Variant 3-53666373-G-A is Benign according to our data. Variant chr3-53666373-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.538 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00393 (599/152294) while in subpopulation NFE AF = 0.00637 (433/68020). AF 95% confidence interval is 0.00587. There are 4 homozygotes in GnomAd4. There are 273 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.954G>A	p.Ala318Ala	synonymous	Exon 7 of 49	NP_000711.1	Q01668-2
	CACNA1D	NM_001128840.3	MANE Select	c.954G>A	p.Ala318Ala	synonymous	Exon 7 of 48	NP_001122312.1	Q01668-1
	CACNA1D	NM_001128839.3		c.954G>A	p.Ala318Ala	synonymous	Exon 7 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.954G>A	p.Ala318Ala	synonymous	Exon 7 of 49	ENSP00000288139.3	Q01668-2
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.954G>A	p.Ala318Ala	synonymous	Exon 7 of 48	ENSP00000288133.5	Q01668-1
	CACNA1D	ENST00000481478.2	TSL:1	c.954G>A	p.Ala318Ala	synonymous	Exon 7 of 49	ENSP00000418014.2	H0Y879

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152176 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00637

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00412 AC: 1035 AN: 251416 AF XY: 0.00442

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00571

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00524 AC: 7665 AN: 1461842 Hom.: 39 Cov.: 33 AF XY: 0.00536 AC XY: 3900 AN XY: 727230

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00268 AC: 120 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00674 AC: 581 AN: 86256

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53420

Middle Eastern (MID) AF: 0.00521 AC: 30 AN: 5754

European-Non Finnish (NFE) AF: 0.00588 AC: 6533 AN: 1111982

Other (OTH) AF: 0.00392 AC: 237 AN: 60390

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152294 Hom.: 4 Cov.: 33 AF XY: 0.00367 AC XY: 273 AN XY: 74470

African (AFR) AF: 0.00111 AC: 46 AN: 41574

American (AMR) AF: 0.00372 AC: 57 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5168

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4822

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00637 AC: 433 AN: 68020

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00524 Hom.: 1

Bravo AF: 0.00347

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Aldosterone-producing adenoma with seizures and neurological abnormalities (1)
-	-	1	CACNA1D-related disorder (1)
-	-	1	Sinoatrial node dysfunction and deafness;C3809609:Aldosterone-producing adenoma with seizures and neurological abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		0.54
PromoterAI		-0.022	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147336902; hg19: chr3-53700400;