16-1218979-C-T

Position:

chr16-1218979-C-T

Variant summary

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

The ENST00000348261.11(CACNA1H):c.5897C>T(p.Ala1966Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,550,154 control chromosomes in the GnomAD database, including 431 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 0.015 ( 29 hom., cov: 31)

Exomes 𝑓: 0.022 ( 402 hom. )

Consequence

CACNA1H
ENST00000348261.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.978

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=0.0041008294).

BP6

Variant 16-1218979-C-T is Benign according to our data. Variant chr16-1218979-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 166781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218979-C-T is described in Lovd as [Benign]. Variant chr16-1218979-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0153 (2328/152242) while in subpopulation SAS AF= 0.0271 (131/4834). AF 95% confidence interval is 0.0233. There are 29 homozygotes in gnomad4. There are 1169 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.5897C>T	p.Ala1966Val	missense_variant	34/35	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.5897C>T	p.Ala1966Val	missense_variant	34/35	1	NM_021098.3	ENSP00000334198	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2327

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00394

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0234

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0170

AC:

2628

AN:

154172

Hom.:

AF XY:

0.0176

AC XY:

1443

AN XY:

82040

show subpopulations

Gnomad AFR exome

AF:

0.00401

Gnomad AMR exome

AF:

0.00743

Gnomad ASJ exome

AF:

0.00768

Gnomad EAS exome

AF:

0.0000922

Gnomad SAS exome

AF:

0.0233

Gnomad FIN exome

AF:

0.0206

Gnomad NFE exome

AF:

0.0239

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0223

AC:

31200

AN:

1397912

Hom.:

402

Cov.:

AF XY:

0.0223

AC XY:

15400

AN XY:

689506

show subpopulations

Gnomad4 AFR exome

AF:

0.00298

Gnomad4 AMR exome

AF:

0.00801

Gnomad4 ASJ exome

AF:

0.00870

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0235

Gnomad4 FIN exome

AF:

0.0207

Gnomad4 NFE exome

AF:

0.0246

Gnomad4 OTH exome

AF:

0.0195

GnomAD4 genome

AF:

0.0153

AC:

2328

AN:

152242

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1169

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00392

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0271

Gnomad4 FIN

AF:

0.0211

Gnomad4 NFE

AF:

0.0234

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0159

Hom.:

Bravo

AF:

0.0132

TwinsUK

AF:

0.0256

AC:

ALSPAC

AF:

0.0252

AC:

ESP6500AA

AF:

0.00475

AC:

ESP6500EA

AF:

0.0202

AC:

133

ExAC

AF:

0.0114

AC:

435

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2017	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2020	- -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 04, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.082

T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.58

T;T;T;.

MetaRNN

Benign

0.0041

T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.90

L;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.050

N;.;N;N

REVEL

Benign

0.29

Sift

Benign

0.30

T;.;T;T

Sift4G

Benign

0.51

T;.;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.045

ClinPred

0.00072

GERP RS

3.5

La Branchor

0.40

Varity_R

0.029

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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