NM_021098.3:c.3970-5G>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.3970-5G>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 0.00012 in 1,609,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.007016

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.397

Publications

1 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=-0.83).

BP6

Variant 16-1210578-G-A is Benign according to our data. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210578-G-A is described in CliVar as Benign. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000342 (52/152254) while in subpopulation EAS AF = 0.00174 (9/5182). AF 95% confidence interval is 0.000906. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3970-5G>A		splice_region_variant, intron_variant	Intron 19 of 34	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3931-5G>A	splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3931-5G>A	splice_region_variant, intron_variant	Intron 19 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.4020-5G>A	splice_region_variant, intron_variant	Intron 19 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1883-5G>A	splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3417-5G>A	splice_region_variant, intron_variant	Intron 18 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3970-5G>A	splice_region_variant, intron_variant	Intron 19 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000253

AC:

AN:

244720

AF XY:

0.000299

show subpopulations

Gnomad AFR exome

AF:

0.000657

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00268

Gnomad FIN exome

AF:

0.0000520

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000968

AC:

141

AN:

1457014

Hom.:

Cov.:

AF XY:

0.0000993

AC XY:

AN XY:

724898

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33474

American (AMR)

AF:

0.0000671

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00189

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000204

AC:

AN:

48920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111756

Other (OTH)

AF:

0.0000995

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000342

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000891

AC:

AN:

41538

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000124

Hom.:

Bravo

AF:

0.000397

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 30, 2017

Athena Diagnostics

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

-0.83

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

0.40

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0070

dbscSNV1_RF

Benign

0.53

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.88

Position offset: 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