rs386834264

Variant names:

• chr3-53673804-G-A
• rs386834264
• NM_000720.4:c.1208G>A
• CACNA1D p.Gly403Asp

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_000720.4(CACNA1D):​c.1208G>A​(p.Gly403Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000238465: Electrophysiological study of this variant showed that it was comparable to a different mutation at amino acid position 403 (p.Gly403Arg) found in an adrenal aldosterone-producing adenoma that is activated at less depolarizing potentials and impairs the inactivation of the wildtype allele (Scholl et al. 2013, PMID:23913001)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1D NM_000720.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0
• Publications: 37 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), Illumina, Ambry Genetics, G2P
• 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), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000238465: Electrophysiological study of this variant showed that it was comparable to a different mutation at amino acid position 403 (p.Gly403Arg) found in an adrenal aldosterone-producing adenoma that is activated at less depolarizing potentials and impairs the inactivation of the wildtype allele (Scholl et al. 2013, PMID: 23913001).; SCV002235250: Experimental studies have shown that this missense change affects CACNA1D function (PMID: 23913001).; SCV002817245: Assessment of experimental evidence suggests this is gain-of-function variant (PMID: 23913001).; SCV006078747: Published functional studies suggest a damaging effect on channel function (PMID: 23913001)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 3-53673804-G-A is Pathogenic according to our data. Variant chr3-53673804-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 66072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000720.4. 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.1208G>A	p.Gly403Asp	missense	Exon 8 of 49	NP_000711.1	Q01668-2
	CACNA1D	NM_001128840.3	MANE Select	c.1220+678G>A		intron	N/A	NP_001122312.1	Q01668-1
	CACNA1D	NM_001128839.3		c.1220+678G>A		intron	N/A	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.1208G>A	p.Gly403Asp	missense	Exon 8 of 49	ENSP00000288139.3	Q01668-2
	CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.1220+678G>A		intron	N/A	ENSP00000288133.5	Q01668-1
	CACNA1D	ENST00000481478.2	TSL:1	c.1220+678G>A		intron	N/A	ENSP00000418014.2	H0Y879

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Aldosterone-producing adenoma with seizures and neurological abnormalities (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.85	D
PhyloP100		10
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
gMVP		0.99
Mutation Taster		=5/95	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs386834264;

hg19: chr3-53707831;