rs59650398

Positions:

chr16-1200446-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.994G>A(p.Ala332Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,611,106 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 33)

Exomes 𝑓: 0.017 ( 282 hom. )

Consequence

CACNA1H
ENST00000348261.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.957

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=0.0031196177).

BP6

Variant 16-1200446-G-A is Benign according to our data. Variant chr16-1200446-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1200446-G-A is described in Lovd as [Benign]. Variant chr16-1200446-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.014 (2135/152254) while in subpopulation SAS AF= 0.0274 (132/4826). AF 95% confidence interval is 0.0236. There are 23 homozygotes in gnomad4. There are 1066 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.994G>A	p.Ala332Thr	missense_variant	7/35	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.994G>A	p.Ala332Thr	missense_variant	7/35	1	NM_021098.3	ENSP00000334198	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2137

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0173

Gnomad ASJ

AF:

0.0510

Gnomad EAS

AF:

0.000775

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.0158

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.0177

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.0168

AC:

4110

AN:

244950

Hom.:

AF XY:

0.0183

AC XY:

2449

AN XY:

133778

show subpopulations

Gnomad AFR exome

AF:

0.00212

Gnomad AMR exome

AF:

0.0105

Gnomad ASJ exome

AF:

0.0471

Gnomad EAS exome

AF:

0.000168

Gnomad SAS exome

AF:

0.0268

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.0201

GnomAD4 exome

AF:

0.0171

AC:

24877

AN:

1458852

Hom.:

282

Cov.:

AF XY:

0.0177

AC XY:

12862

AN XY:

725818

show subpopulations

Gnomad4 AFR exome

AF:

0.00275

Gnomad4 AMR exome

AF:

0.0114

Gnomad4 ASJ exome

AF:

0.0461

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0278

Gnomad4 FIN exome

AF:

0.0147

Gnomad4 NFE exome

AF:

0.0167

Gnomad4 OTH exome

AF:

0.0194

GnomAD4 genome

AF:

0.0140

AC:

2135

AN:

152254

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1066

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00318

Gnomad4 AMR

AF:

0.0173

Gnomad4 ASJ

AF:

0.0510

Gnomad4 EAS

AF:

0.000777

Gnomad4 SAS

AF:

0.0274

Gnomad4 FIN

AF:

0.0158

Gnomad4 NFE

AF:

0.0177

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.0191

Hom.:

Bravo

AF:

0.0133

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00190

AC:

ESP6500EA

AF:

0.0173

AC:

145

ExAC

AF:

0.0166

AC:

2000

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Epilepsy, childhood absence, susceptibility to, 6

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Uncertain significance and reported on 09/25/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

0.20

DANN

Benign

0.95

DEOGEN2

Benign

0.34

T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.75

T;T;T;.

MetaRNN

Benign

0.0031

T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

-0.40

N;.;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

0.36

N;.;N;N

REVEL

Benign

0.21

Sift

Benign

0.44

T;.;T;T

Sift4G

Benign

0.75

T;.;T;T

Polyphen

0.0080

B;.;B;B

Vest4

0.15

ClinPred

0.00054

GERP RS

3.2

Varity_R

0.049

gMVP

0.75

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