NM_021098.3:c.4224-6C>T

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.4224-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,612,572 control chromosomes in the GnomAD database, including 18 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 10 hom., cov: 35)

Exomes 𝑓: 0.00064 ( 8 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.00003067

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.33

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=-0.84).

BP6

Variant 16-1211162-C-T is Benign according to our data. Variant chr16-1211162-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460110.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 = 0.0053 (808/152334) while in subpopulation AFR AF = 0.0179 (744/41578). AF 95% confidence interval is 0.0168. There are 10 homozygotes in GnomAd4. There are 342 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAd4 at 808 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4224-6C>T		splice_region_variant, intron_variant	Intron 21 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.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4185-6C>T	splice_region_variant, intron_variant	Intron 21 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4185-6C>T	splice_region_variant, intron_variant	Intron 21 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*194-6C>T	splice_region_variant, intron_variant	Intron 21 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2137-6C>T	splice_region_variant, intron_variant	Intron 21 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3671-6C>T	splice_region_variant, intron_variant	Intron 20 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4224-6C>T	splice_region_variant, intron_variant	Intron 21 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00529

AC:

805

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00150

AC:

371

AN:

247306

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.0197

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000986

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000642

AC:

937

AN:

1460238

Hom.:

Cov.:

AF XY:

0.000575

AC XY:

418

AN XY:

726418

show subpopulations

African (AFR)

AF:

0.0195

AC:

654

AN:

33472

American (AMR)

AF:

0.00183

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52258

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000810

AC:

AN:

1111658

Other (OTH)

AF:

0.00159

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00530

AC:

808

AN:

152334

Hom.:

Cov.:

AF XY:

0.00459

AC XY:

342

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0179

AC:

744

AN:

41578

American (AMR)

AF:

0.00287

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68034

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

120

160

200

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:

0.00240

Hom.:

Bravo

AF:

0.00660

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 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

-0.84

CADD

Benign

0.035

(source)

DANN

Benign

0.58

PhyloP100

-2.3

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.020

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