rs58173258

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(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
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:2

Conservation

PhyloP100: 1.18

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hyperaldosteronism, familial, type IV
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
childhood absence epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, childhood absence, susceptibility to, 6
Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 2706.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 247 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.2587G>A	p.Ala863Thr	missense_variant	Exon 12 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.2587G>A	p.Ala863Thr	missense_variant	Exon 12 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*539G>A		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2073G>A		non_coding_transcript_exon_variant	Exon 11 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*539G>A		3_prime_UTR_variant	Exon 12 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2073G>A		3_prime_UTR_variant	Exon 11 of 34			ENSP00000518758.1

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

GnomAD2 exomes

AF:

0.00117

AC:

236

AN:

201770

AF XY:

0.00112

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 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

African (AFR)

AF:

0.000304

AC:

AN:

32932

American (AMR)

AF:

0.00260

AC:

108

AN:

41472

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

25544

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38238

South Asian (SAS)

AF:

0.00

AC:

AN:

81528

European-Finnish (FIN)

AF:

0.000212

AC:

AN:

47198

Middle Eastern (MID)

AF:

0.000373

AC:

AN:

5356

European-Non Finnish (NFE)

AF:

0.00183

AC:

2013

AN:

1099792

Other (OTH)

AF:

0.00145

AC:

AN:

59298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

125

249

374

498

623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00162

AC:

247

AN:

152358

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

130

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41588

American (AMR)

AF:

0.00372

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000658

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00171

AC:

116

AN:

68020

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000549

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:1Benign:4Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6

Uncertain:1Other:1

Jan 18, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

GenomeConnect - Brain Gene Registry

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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/. -

not specified

Benign:1

Jan 10, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA1H-related disorder

Benign:1

Apr 11, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1, BS2 -

Epilepsy, idiopathic generalized, susceptibility to, 6

Other:1

Dec 01, 2007

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

(source)

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

PhyloP100

1.2

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

Mutation Taster

=73/27

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over