Variant rs58667649 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_021098.3(CACNA1H):c.5675G>A(p.Arg1892His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,552,680 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1892L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00020 ( 3 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.683

Variant links:

Genes affected

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02485764).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000158 (24/152308) while in subpopulation SAS AF= 0.00145 (7/4824). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.5675G>A	p.Arg1892His	missense_variant	33/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.5675G>A	p.Arg1892His	missense_variant	33/35	1	NM_021098.3	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000341

AC:

AN:

158130

Hom.:

AF XY:

0.000393

AC XY:

AN XY:

83868

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000804

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.000182

Gnomad SAS exome

AF:

0.00153

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000198

AC:

277

AN:

1400372

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

173

AN XY:

690952

show subpopulations

Gnomad4 AFR exome

AF:

0.0000631

Gnomad4 AMR exome

AF:

0.0000557

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000837

Gnomad4 SAS exome

AF:

0.00174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000861

Gnomad4 OTH exome

AF:

0.000412

GnomAD4 genome

AF:

0.000158

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000178

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000196

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.24

CADD

Benign

7.0

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.61

T;T;T;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.025

T;T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

0.34

N;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.32

N;.;N;N

REVEL

Benign

0.29

Sift

Benign

0.12

T;.;T;T

Sift4G

Benign

0.11

T;.;T;T

Polyphen

0.70

P;.;D;D

Vest4

0.12

MVP

0.69

ClinPred

0.010

GERP RS

-0.61

Varity_R

0.053

gMVP

0.29

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