rs58173258

Positions:

chr16-1206126-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000348261.11(CACNA1H):c.2626G>A(p.Ala876Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,583,716 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A876V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

CACNA1H
ENST00000348261.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3O:2

Conservation

PhyloP100: 1.18

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01942408).

BP6

Variant 16-1206126-G-A is Benign according to our data. Variant chr16-1206126-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2706.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2, not_provided=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00162 (247/152358) while in subpopulation AMR AF= 0.00372 (57/15310). AF 95% confidence interval is 0.00295. There are 0 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 247 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.2626G>A	p.Ala876Thr	missense_variant	12/35	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.2626G>A	p.Ala876Thr	missense_variant	12/35	1	NM_021098.3	ENSP00000334198	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

247

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.0451

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000658

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00117

AC:

236

AN:

201770

Hom.:

AF XY:

0.00112

AC XY:

123

AN XY:

109902

show subpopulations

Gnomad AFR exome

AF:

0.000535

Gnomad AMR exome

AF:

0.00255

Gnomad ASJ exome

AF:

0.00142

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000622

Gnomad NFE exome

AF:

0.00136

Gnomad OTH exome

AF:

0.00154

GnomAD4 exome

AF:

0.00158

AC:

2260

AN:

1431358

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1048

AN XY:

709606

show subpopulations

Gnomad4 AFR exome

AF:

0.000304

Gnomad4 AMR exome

AF:

0.00260

Gnomad4 ASJ exome

AF:

0.00117

Gnomad4 EAS exome

AF:

0.0000262

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000212

Gnomad4 NFE exome

AF:

0.00183

Gnomad4 OTH exome

AF:

0.00145

GnomAD4 genome

AF:

0.00162

AC:

247

AN:

152358

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

130

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00372

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000658

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000482

Hom.:

Bravo

AF:

0.00188

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000729

AC:

ESP6500EA

AF:

0.00155

AC:

ExAC

AF:

0.000835

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CACNA1H: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2021	- -

Epilepsy, childhood absence, susceptibility to, 6

Uncertain:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Uncertain significance and reported on 05-31-2019 by Sema4. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Philip Payne PhD, FACMI from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 18, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

CACNA1H-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2020

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Epilepsy, idiopathic generalized, susceptibility to, 6

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

D;D;D;.

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.019

T;T;T;T

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.2

L;.;L;L

MutationTaster

Benign

0.74

N;N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.5

N;.;N;N

REVEL

Pathogenic

0.66

Sift

Benign

0.55

T;.;T;T

Sift4G

Benign

0.17

T;.;T;T

Polyphen

0.89

P;.;D;D

Vest4

0.35

MVP

0.99

ClinPred

0.036

GERP RS

2.9

Varity_R

0.11

gMVP

0.61

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