Variant 22-39570834-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The ENST00000402142.4(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
ENST00000402142.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.91

Variant links:

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]

CACNA1I links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1I. . Gene score misZ 5.0511 (greater than the threshold 3.09). Trascript score misZ 3.2896 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, neurodevelopmental disorder with speech impairment and with or without seizures.

BP4

Computational evidence support a benign effect (MetaRNN=0.19354752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4 linkuse as main transcript	c.82C>T	p.Pro28Ser	missense_variant	1/37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2 linkuse as main transcript	c.82C>T	p.Pro28Ser	missense_variant	1/36		NP_001003406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4 linkuse as main transcript	c.82C>T	p.Pro28Ser	missense_variant	1/37	1	NM_021096.4	ENSP00000385019	A2	Q9P0X4-1
CACNA1I	ENST00000404898.5 linkuse as main transcript	c.82C>T	p.Pro28Ser	missense_variant	1/36	1		ENSP00000384093	A2	Q9P0X4-4
CACNA1I	ENST00000401624.5 linkuse as main transcript	c.82C>T	p.Pro28Ser	missense_variant	1/36	1		ENSP00000383887	P4	Q9P0X4-2
CACNA1I	ENST00000407673.5 linkuse as main transcript	c.82C>T	p.Pro28Ser	missense_variant	1/35	1		ENSP00000385680	A2	Q9P0X4-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461268

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726964

show subpopulations

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.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CACNA1I-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2024

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

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

.;.;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.59

T;T;T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.90

L;L;L;L

MutationTaster

Benign

0.77

D;D;D;D;D;D

PrimateAI

Benign

0.45

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over