chr22-39570820-C-T

Position:

chr22-39570820-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The ENST00000402142.4(CACNA1I):c.68C>T(p.Thr23Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CACNA1I
ENST00000402142.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.935

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 Likely_benign. Variant got -5 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=0.13810259).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4 linkuse as main transcript	c.68C>T	p.Thr23Met	missense_variant	1/37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2 linkuse as main transcript	c.68C>T	p.Thr23Met	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.68C>T	p.Thr23Met	missense_variant	1/37	1	NM_021096.4	ENSP00000385019	A2	Q9P0X4-1
CACNA1I	ENST00000404898.5 linkuse as main transcript	c.68C>T	p.Thr23Met	missense_variant	1/36	1		ENSP00000384093	A2	Q9P0X4-4
CACNA1I	ENST00000401624.5 linkuse as main transcript	c.68C>T	p.Thr23Met	missense_variant	1/36	1		ENSP00000383887	P4	Q9P0X4-2
CACNA1I	ENST00000407673.5 linkuse as main transcript	c.68C>T	p.Thr23Met	missense_variant	1/35	1		ENSP00000385680	A2	Q9P0X4-3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000446

AC:

AN:

246574

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

134140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461158

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000413

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Jan 16, 2024

The c.68C>T (p.T23M) alteration is located in exon 1 (coding exon 1) of the CACNA1I gene. This alteration results from a C to T substitution at nucleotide position 68, causing the threonine (T) at amino acid position 23 to be replaced by a methionine (M). 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

0.10

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

.;.;.;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.52

T;T;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Uncertain

0.072

MutationAssessor

Benign

1.1

L;L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.19

N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.62, 0.49

.;.;P;P

Vest4

0.077

MVP

0.56

MPC

1.6

ClinPred

0.11

GERP RS

5.3

Varity_R

0.019

gMVP

0.36

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