3-53811268-C-T

Variant names:

• chr3-53811268-C-T
• rs10154841
• NM_000720.4:c.6408C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001128840.3(CACNA1D):​c.6348C>T​(p.Asn2116Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,576 control chromosomes in the GnomAD database, including 20,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (7753 hom., cov: 32)
  • Exomes 𝑓: 0.11 (13111 hom.)
• Consequence: CACNA1D NM_001128840.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.12
• Publications: 18 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=-0.68).
• BP6: Variant 3-53811268-C-T is Benign according to our data. Variant chr3-53811268-C-T is described in ClinVar as Benign. ClinVar VariationId is 226478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 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.6408C>T	p.Asn2136Asn	synonymous	Exon 49 of 49	NP_000711.1	Q01668-2
	CACNA1D	NM_001128840.3	MANE Select	c.6348C>T	p.Asn2116Asn	synonymous	Exon 48 of 48	NP_001122312.1	Q01668-1
	CACNA1D	NM_001128839.3		c.6276C>T	p.Asn2092Asn	synonymous	Exon 46 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.6408C>T	p.Asn2136Asn	synonymous	Exon 49 of 49	ENSP00000288139.3	Q01668-2
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.6348C>T	p.Asn2116Asn	synonymous	Exon 48 of 48	ENSP00000288133.5	Q01668-1
	CACNA1D	ENST00000481478.2	TSL:1	c.6408C>T	p.Asn2136Asn	synonymous	Exon 49 of 49	ENSP00000418014.2	H0Y879

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35496 AN: 151954 Hom.: 7729 Cov.: 32

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0854

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.134 AC: 33631 AN: 251278 AF XY: 0.124

Gnomad AFR exome AF: 0.595

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.0878

Gnomad NFE exome AF: 0.0863

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.107 AC: 155982 AN: 1461502 Hom.: 13111 Cov.: 32 AF XY: 0.105 AC XY: 76302 AN XY: 727060

African (AFR) AF: 0.600 AC: 20086 AN: 33474

American (AMR) AF: 0.132 AC: 5895 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3571 AN: 26134

East Asian (EAS) AF: 0.162 AC: 6436 AN: 39700

South Asian (SAS) AF: 0.104 AC: 8931 AN: 86254

European-Finnish (FIN) AF: 0.0867 AC: 4611 AN: 53200

Middle Eastern (MID) AF: 0.128 AC: 734 AN: 5748

European-Non Finnish (NFE) AF: 0.0881 AC: 97937 AN: 1111884

Other (OTH) AF: 0.129 AC: 7781 AN: 60394

GnomAD4 genome AF: 0.234 AC: 35567 AN: 152074 Hom.: 7753 Cov.: 32 AF XY: 0.231 AC XY: 17165 AN XY: 74348

African (AFR) AF: 0.584 AC: 24199 AN: 41412

American (AMR) AF: 0.152 AC: 2318 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 496 AN: 3472

East Asian (EAS) AF: 0.140 AC: 722 AN: 5158

South Asian (SAS) AF: 0.117 AC: 563 AN: 4820

European-Finnish (FIN) AF: 0.0904 AC: 957 AN: 10586

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0853 AC: 5805 AN: 68020

Other (OTH) AF: 0.210 AC: 444 AN: 2114

Alfa AF: 0.174 Hom.: 8655

Bravo AF: 0.256

Asia WGS AF: 0.162 AC: 565 AN: 3478

EpiCase AF: 0.0931

EpiControl AF: 0.0905

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.16
DANN	Benign	0.63
PhyloP100		-2.1
Mutation Taster		=92/8	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: rs10154841; hg19: chr3-53845295; COSMIC: COSV55437874; COSMIC: COSV55437874;