3-53730470-C-G

Position:

• chr3-53730470-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000720.4(CACNA1D):​c.2310C>G​(p.Ile770Met) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I770F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1D NM_000720.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -0.00800

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000720.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-53730468-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 801978.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1D. . Gene score misZ 4.5817 (greater than the threshold 3.09). Trascript score misZ 6.6047 (greater than threshold 3.09). GenCC has associacion of gene with sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 3-53730470-C-G is Pathogenic according to our data. Variant chr3-53730470-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66073.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-53730470-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.2310C>G	p.Ile770Met	missense_variant	17/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.2250C>G	p.Ile750Met	missense_variant	16/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.2310C>G	p.Ile770Met	missense_variant	17/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.2250C>G	p.Ile750Met	missense_variant	16/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Aldosterone-producing adenoma with seizures and neurological abnormalities Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2013

- -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Richard Lifton Laboratory, Yale University School of Medicine

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;.;.;.;.;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	-0.022
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;H;.;.;.;H;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	.;D;.;.;D;D;.;.;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	.;D;.;.;D;D;.;.;D
Sift4G	Pathogenic	0.0	.;D;.;.;D;D;.;.;D
Polyphen		1.0	.;D;.;D;D;.;.;.;D
Vest4		0.97, 0.97, 0.96
MutPred		0.69		.;Loss of catalytic residue at D753 (P = 0.1704);Loss of catalytic residue at D753 (P = 0.1704);.;.;Loss of catalytic residue at D753 (P = 0.1704);Loss of catalytic residue at D753 (P = 0.1704);.;.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		-2.1
Varity_R		0.66
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs41276445; hg19: chr3-53764497; COSMIC: COSV55445379; COSMIC: COSV55445379;