rs187596702

Positions:

chr16-1195057-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000348261.11(CACNA1H):c.385G>A(p.Gly129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,608,740 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

CACNA1H
ENST00000348261.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.369

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022167772).

BP6

Variant 16-1195057-G-A is Benign according to our data. Variant chr16-1195057-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1195057-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000982 (149/151674) while in subpopulation AFR AF= 0.00327 (135/41310). AF 95% confidence interval is 0.00282. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High AC in GnomAd4 at 149 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.385G>A	p.Gly129Ser	missense_variant	3/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.385G>A	p.Gly129Ser	missense_variant	3/35	1	NM_021098.3	ENSP00000334198	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.000977

AC:

148

AN:

151558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000789

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:

0.000961

GnomAD3 exomes

AF:

0.000254

AC:

AN:

247930

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

134876

show subpopulations

Gnomad AFR exome

AF:

0.00344

Gnomad AMR exome

AF:

0.000203

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:

0.0000178

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000132

AC:

193

AN:

1457066

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

724158

show subpopulations

Gnomad4 AFR exome

AF:

0.00437

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000902

Gnomad4 OTH exome

AF:

0.000382

GnomAD4 genome

AF:

0.000982

AC:

149

AN:

151674

Hom.:

Cov.:

AF XY:

0.000890

AC XY:

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.00327

Gnomad4 AMR

AF:

0.000788

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:

0.000951

Alfa

AF:

0.0320

Hom.:

2342

Bravo

AF:

0.00137

ESP6500AA

AF:

0.00357

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000256

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.34

T;.;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.67

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.76

T;T;T;.

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.022

T;T;T;T

MetaSVM

Uncertain

0.034

MutationAssessor

Benign

0.0

N;.;N;N

MutationTaster

Benign

0.98

N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

0.87

N;.;N;N

REVEL

Benign

0.29

Sift

Benign

0.71

T;.;T;T

Sift4G

Benign

0.73

T;.;T;T

Polyphen

0.12

B;.;P;P

Vest4

0.26

MVP

0.63

ClinPred

0.0084

GERP RS

3.5

Varity_R

0.029

gMVP

0.25

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