rs57315342

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.4039-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,599,932 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 3 hom., cov: 35)

Exomes 𝑓: 0.0035 ( 36 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.00001501

Clinical Significance

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

Conservation

PhyloP100: -1.75

Publications

2 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 (BayesDel_noAF=-0.91).

BP6

Variant 16-1210783-G-A is Benign according to our data. Variant chr16-1210783-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460106.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00293 (446/152358) while in subpopulation SAS AF = 0.00435 (21/4832). AF 95% confidence interval is 0.00312. There are 3 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAd4 at 446 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4039-4G>A		splice_region_variant, intron_variant	Intron 20 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4000-4G>A	splice_region_variant, intron_variant	Intron 20 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4000-4G>A	splice_region_variant, intron_variant	Intron 20 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*9-4G>A	splice_region_variant, intron_variant	Intron 20 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*1952-4G>A	splice_region_variant, intron_variant	Intron 20 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3486-4G>A	splice_region_variant, intron_variant	Intron 19 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4039-4G>A	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

446

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00348

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00359

AC:

849

AN:

236414

AF XY:

0.00378

show subpopulations

Gnomad AFR exome

AF:

0.000332

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.0298

Gnomad EAS exome

AF:

0.0000561

Gnomad FIN exome

AF:

0.000154

Gnomad NFE exome

AF:

0.00316

Gnomad OTH exome

AF:

0.00644

GnomAD4 exome

AF:

0.00355

AC:

5133

AN:

1447574

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

2628

AN XY:

720622

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33468

American (AMR)

AF:

0.00186

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.0327

AC:

852

AN:

26088

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39678

South Asian (SAS)

AF:

0.00372

AC:

321

AN:

86210

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

40016

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00315

AC:

3498

AN:

1111460

Other (OTH)

AF:

0.00475

AC:

286

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

288

576

863

1151

1439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.00293

AC:

446

AN:

152358

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

203

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41578

American (AMR)

AF:

0.00216

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00435

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00348

AC:

237

AN:

68028

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00554

Hom.:

Bravo

AF:

0.00289

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BP4, BS2 -

Oct 06, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 05, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA1H-related disorder

Benign:1

Apr 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.13

(source)

DANN

Benign

0.53

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.020

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