NM_021098.3:c.5324-4G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.5324-4G>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 0.00103 in 1,598,276 control chromosomes in the GnomAD database, including 12 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 4 hom., cov: 34)

Exomes 𝑓: 0.00060 ( 8 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.00001647

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.23

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-1217915-G-A is Benign according to our data. Variant chr16-1217915-G-A is described in ClinVar as Benign. ClinVar VariationId is 529687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00515 (785/152320) while in subpopulation AFR AF = 0.0173 (721/41572). AF 95% confidence interval is 0.0163. There are 4 homozygotes in GnomAd4. There are 368 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 785 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5324-4G>A		splice_region_variant, intron_variant	Intron 31 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.5324-4G>A	splice_region_variant, intron_variant	Intron 31 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.5339-4G>A	splice_region_variant, intron_variant	Intron 30 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.5342-4G>A	splice_region_variant, intron_variant	Intron 30 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5306-4G>A	splice_region_variant, intron_variant	Intron 30 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.5339-4G>A	splice_region_variant, intron_variant	Intron 31 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5324-4G>A	splice_region_variant, intron_variant	Intron 31 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.5285-4G>A	splice_region_variant, intron_variant	Intron 31 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.5306-4G>A	splice_region_variant, intron_variant	Intron 30 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.5267-4G>A	splice_region_variant, intron_variant	Intron 30 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5324-4G>A	splice_region_variant, intron_variant	Intron 31 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5306-4G>A	splice_region_variant, intron_variant	Intron 30 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5324-4G>A	splice_region_variant, intron_variant	Intron 31 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5324-4G>A	splice_region_variant, intron_variant	Intron 31 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5324-4G>A	splice_region_variant, intron_variant	Intron 31 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5324-4G>A	splice_region_variant, intron_variant	Intron 31 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1276-4G>A	splice_region_variant, intron_variant	Intron 30 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*405-4G>A	splice_region_variant, intron_variant	Intron 31 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*3175-4G>A	splice_region_variant, intron_variant	Intron 31 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*4768-4G>A	splice_region_variant, intron_variant	Intron 29 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*298-4G>A	splice_region_variant, intron_variant	Intron 32 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*183-4G>A	splice_region_variant, intron_variant	Intron 31 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*936-4G>A	splice_region_variant, intron_variant	Intron 32 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5439-4G>A	splice_region_variant, intron_variant	Intron 32 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5352-4G>A	splice_region_variant, intron_variant	Intron 32 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5306-4G>A	splice_region_variant, intron_variant	Intron 30 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5324-4G>A	splice_region_variant, intron_variant	Intron 31 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5324-4G>A	splice_region_variant, intron_variant	Intron 31 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*440-4G>A	splice_region_variant, intron_variant	Intron 31 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00516

AC:

785

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00113

AC:

253

AN:

223638

AF XY:

0.000833

show subpopulations

Gnomad AFR exome

AF:

0.0168

Gnomad AMR exome

AF:

0.000772

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000609

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000602

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000600

AC:

867

AN:

1445956

Hom.:

Cov.:

AF XY:

0.000496

AC XY:

356

AN XY:

717926

show subpopulations

African (AFR)

AF:

0.0188

AC:

621

AN:

33104

American (AMR)

AF:

0.00105

AC:

AN:

43048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25812

East Asian (EAS)

AF:

0.0000774

AC:

AN:

38752

South Asian (SAS)

AF:

0.000143

AC:

AN:

83796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50760

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000102

AC:

113

AN:

1105232

Other (OTH)

AF:

0.00111

AC:

AN:

59718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00515

AC:

785

AN:

152320

Hom.:

Cov.:

AF XY:

0.00494

AC XY:

368

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0173

AC:

721

AN:

41572

American (AMR)

AF:

0.00255

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68022

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

101

135

169

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:

0.00250

Hom.:

Bravo

AF:

0.00623

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Aug 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 22, 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

-0.85

CADD

Benign

0.070

(source)

DANN

Benign

0.71

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000016

dbscSNV1_RF

Benign

0.0020

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