Variant chr22-39600562-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021096.4(CACNA1I):c.391G>T(p.Val131Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

CACNA1I
NM_021096.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.51

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:

Genome browser will be placed here

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;

BP4

Computational evidence support a benign effect (MetaRNN=0.4116054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4 link	c.391G>T	p.Val131Leu	missense_variant	3/37	ENST00000402142.4	NP_066919.2	Q9P0X4-1
CACNA1I	NM_001003406.2 link	c.391G>T	p.Val131Leu	missense_variant	3/36		NP_001003406.1	Q9P0X4-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1I	ENST00000402142.4 link	c.391G>T	p.Val131Leu	missense_variant	3/37	1	NM_021096.4	ENSP00000385019.3	Q9P0X4-1
CACNA1I	ENST00000404898.5 link	c.391G>T	p.Val131Leu	missense_variant	3/36	1		ENSP00000384093.1	Q9P0X4-4
CACNA1I	ENST00000401624.5 link	c.391G>T	p.Val131Leu	missense_variant	3/36	1		ENSP00000383887.1	Q9P0X4-2
CACNA1I	ENST00000407673.5 link	c.391G>T	p.Val131Leu	missense_variant	3/35	1		ENSP00000385680.1	Q9P0X4-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.391G>T (p.V131L) alteration is located in exon 3 (coding exon 3) of the CACNA1I gene. This alteration results from a G to T substitution at nucleotide position 391, causing the valine (V) at amino acid position 131 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

.;.;.;D

Eigen

Benign

-0.085

Eigen_PC

Benign

0.098

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Uncertain

0.76

MutationAssessor

Benign

1.2

L;L;L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.17

T;T;T;T

Sift4G

Benign

0.082

T;T;T;T

Polyphen

0.0030

B;B;B;P

Vest4

0.54

MutPred

0.64

Loss of catalytic residue at V131 (P = 0.0809);Loss of catalytic residue at V131 (P = 0.0809);Loss of catalytic residue at V131 (P = 0.0809);Loss of catalytic residue at V131 (P = 0.0809);

MVP

0.85

MPC

0.95

ClinPred

0.83

GERP RS

4.7

Varity_R

0.27

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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