22-39570874-C-A

Position:

chr22-39570874-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The ENST00000402142.4(CACNA1I):c.122C>A(p.Pro41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,642 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

CACNA1I
ENST00000402142.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.08

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 Benign. Variant got -7 ACMG points.

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=0.06654394).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4 linkuse as main transcript	c.122C>A	p.Pro41His	missense_variant	1/37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2 linkuse as main transcript	c.122C>A	p.Pro41His	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.122C>A	p.Pro41His	missense_variant	1/37	1	NM_021096.4	ENSP00000385019	A2	Q9P0X4-1
CACNA1I	ENST00000404898.5 linkuse as main transcript	c.122C>A	p.Pro41His	missense_variant	1/36	1		ENSP00000384093	A2	Q9P0X4-4
CACNA1I	ENST00000401624.5 linkuse as main transcript	c.122C>A	p.Pro41His	missense_variant	1/36	1		ENSP00000383887	P4	Q9P0X4-2
CACNA1I	ENST00000407673.5 linkuse as main transcript	c.122C>A	p.Pro41His	missense_variant	1/35	1		ENSP00000385680	A2	Q9P0X4-3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000157

AC:

AN:

248990

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000608

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000118

AC:

173

AN:

1461486

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000761

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

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

Apr 07, 2022

The c.122C>A (p.P41H) alteration is located in exon 1 (coding exon 1) of the CACNA1I gene. This alteration results from a C to A substitution at nucleotide position 122, causing the proline (P) at amino acid position 41 to be replaced by a histidine (H). 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

Benign

0.086

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

.;.;.;T

Eigen

Benign

0.013

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.61

T;T;T;T

M_CAP

Benign

0.072

MetaRNN

Benign

0.067

T;T;T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

1.4

L;L;L;L

MutationTaster

Benign

0.99

N;N;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.059

T;T;T;T

Sift4G

Uncertain

0.052

T;T;T;D

Polyphen

0.55, 0.41

.;.;P;B

Vest4

0.29

MutPred

0.29

Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);

MVP

0.67

MPC

1.9

ClinPred

0.064

GERP RS

4.7

Varity_R

0.10

gMVP

0.40

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