chr22-39570834-C-T

Variant names:

• chr22-39570834-C-T
• rs1932156468
• NM_021096.4:c.82C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021096.4(CACNA1I):​c.82C>T​(p.Pro28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1I NM_021096.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.91

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19354752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.82C>T	p.Pro28Ser	missense_variant	Exon 1 of 37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.82C>T	p.Pro28Ser	missense_variant	Exon 1 of 36		NP_001003406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.82C>T	p.Pro28Ser	missense_variant	Exon 1 of 37	1	NM_021096.4	ENSP00000385019.3
CACNA1I	ENST00000404898.5	c.82C>T	p.Pro28Ser	missense_variant	Exon 1 of 36	1		ENSP00000384093.1
CACNA1I	ENST00000401624.5	c.82C>T	p.Pro28Ser	missense_variant	Exon 1 of 36	1		ENSP00000383887.1
CACNA1I	ENST00000407673.5	c.82C>T	p.Pro28Ser	missense_variant	Exon 1 of 35	1		ENSP00000385680.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461268 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

CACNA1I-related disorder Uncertain:1

Jun 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CACNA1I c.82C>T variant is predicted to result in the amino acid substitution p.Pro28Ser. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating it is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	.;.;.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.90	L;L;L;L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.65, 0.91	.;.;P;P
Vest4		0.12
MutPred		0.22		Gain of phosphorylation at P28 (P = 0.0024);Gain of phosphorylation at P28 (P = 0.0024);Gain of phosphorylation at P28 (P = 0.0024);Gain of phosphorylation at P28 (P = 0.0024);
MVP		0.53
MPC		1.4
ClinPred		0.83	D
GERP RS		4.2
Varity_R		0.041
gMVP		0.50

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: rs1932156468; hg19: chr22-39966839;