3-53803483-C-T

Variant names:

• chr3-53803483-C-T
• rs149746093
• NM_000720.4:c.5556C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001128840.3(CACNA1D):​c.5496C>T​(p.Gly1832Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,613,954 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (3 hom.)
• Consequence: CACNA1D NM_001128840.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.187
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-53803483-C-T is Benign according to our data. Variant chr3-53803483-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 227202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.187 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000932 (142/152358) while in subpopulation NFE AF = 0.00163 (111/68034). AF 95% confidence interval is 0.00138. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.5556C>T	p.Gly1852Gly	synonymous	Exon 45 of 49	NP_000711.1	Q01668-2
	CACNA1D	NM_001128840.3	MANE Select	c.5496C>T	p.Gly1832Gly	synonymous	Exon 44 of 48	NP_001122312.1	Q01668-1
	CACNA1D	NM_001128839.3		c.5424C>T	p.Gly1808Gly	synonymous	Exon 42 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.5556C>T	p.Gly1852Gly	synonymous	Exon 45 of 49	ENSP00000288139.3	Q01668-2
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.5496C>T	p.Gly1832Gly	synonymous	Exon 44 of 48	ENSP00000288133.5	Q01668-1
	CACNA1D	ENST00000481478.2	TSL:1	c.5556C>T	p.Gly1852Gly	synonymous	Exon 45 of 49	ENSP00000418014.2	H0Y879

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000919 AC: 231 AN: 251486 AF XY: 0.000861

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00209 AC: 3048 AN: 1461596 Hom.: 3 Cov.: 32 AF XY: 0.00203 AC XY: 1474 AN XY: 727136

African (AFR) AF: 0.000299 AC: 10 AN: 33474

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00263 AC: 2923 AN: 1111746

Other (OTH) AF: 0.00116 AC: 70 AN: 60390

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74502

African (AFR) AF: 0.000481 AC: 20 AN: 41594

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68034

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.000892

EpiCase AF: 0.00109

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	CACNA1D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.7
DANN	Benign	0.38
PhyloP100		-0.19
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: rs149746093; hg19: chr3-53837510;