chr22-39600615-C-A

Position:

• chr22-39600615-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021096.4(CACNA1I):​c.444C>A​(p.Asp148Glu) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1I NM_021096.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

Genes affected

CACNA1I (HGNC:1396): (calcium voltage-gated channel subunit alpha1 I) This gene encodes the pore-forming alpha subunit of a voltage gated calcium channel. The encoded protein is a member of a subfamily of calcium channels referred to as is a low voltage-activated, T-type, calcium channel. The channel encoded by this protein is characterized by a slower activation and inactivation compared to other T-type calcium channels. This protein may be involved in calcium signaling in neurons. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.444C>A	p.Asp148Glu	missense_variant	3/37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.444C>A	p.Asp148Glu	missense_variant	3/36		NP_001003406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.444C>A	p.Asp148Glu	missense_variant	3/37	1	NM_021096.4	ENSP00000385019.3
CACNA1I	ENST00000404898.5	c.444C>A	p.Asp148Glu	missense_variant	3/36	1		ENSP00000384093.1
CACNA1I	ENST00000401624.5	c.444C>A	p.Asp148Glu	missense_variant	3/36	1		ENSP00000383887.1
CACNA1I	ENST00000407673.5	c.444C>A	p.Asp148Glu	missense_variant	3/35	1		ENSP00000385680.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;.;.;D
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.048	D;T;D;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.0030	B;B;B;D
Vest4		0.84
MutPred		0.59		Loss of ubiquitination at K143 (P = 0.1268);Loss of ubiquitination at K143 (P = 0.1268);Loss of ubiquitination at K143 (P = 0.1268);Loss of ubiquitination at K143 (P = 0.1268);
MVP		0.95
MPC		1.6
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.33
gMVP		0.88

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: rs1933004857; hg19: chr22-39996620;