NM_021098.3:c.1120-8C>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.1120-8C>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 0.0117 in 1,565,138 control chromosomes in the GnomAD database, including 139 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 0.0091 ( 12 hom., cov: 32)

Exomes 𝑓: 0.012 ( 127 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.00007083

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.01

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:

LOC124903623 (HGNC:):

LOC124903623 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=-0.8).

BP6

Variant 16-1200708-C-T is Benign according to our data. Variant chr16-1200708-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00913 (1387/151962) while in subpopulation NFE AF = 0.0147 (997/68022). AF 95% confidence interval is 0.0139. There are 12 homozygotes in GnomAd4. There are 638 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1387 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1120-8C>T		splice_region_variant, intron_variant	Intron 7 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.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1081-8C>T	splice_region_variant, intron_variant	Intron 7 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1081-8C>T	splice_region_variant, intron_variant	Intron 7 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*567-8C>T	splice_region_variant, intron_variant	Intron 6 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.1120-8C>T	splice_region_variant, intron_variant	Intron 7 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00914

AC:

1388

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00232

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.00873

AC:

1522

AN:

174388

AF XY:

0.00918

show subpopulations

Gnomad AFR exome

AF:

0.00268

Gnomad AMR exome

AF:

0.00749

Gnomad ASJ exome

AF:

0.00183

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00427

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.0107

GnomAD4 exome

AF:

0.0120

AC:

16976

AN:

1413176

Hom.:

127

Cov.:

AF XY:

0.0120

AC XY:

8380

AN XY:

698874

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

32062

American (AMR)

AF:

0.00716

AC:

267

AN:

37274

Ashkenazi Jewish (ASJ)

AF:

0.00205

AC:

AN:

25338

East Asian (EAS)

AF:

0.00

AC:

AN:

36648

South Asian (SAS)

AF:

0.00737

AC:

599

AN:

81276

European-Finnish (FIN)

AF:

0.00407

AC:

201

AN:

49332

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

0.0139

AC:

15149

AN:

1087104

Other (OTH)

AF:

0.0101

AC:

591

AN:

58618

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

795

1590

2384

3179

3974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

570

1140

1710

2280

2850

<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:

0.00913

AC:

1387

AN:

151962

Hom.:

Cov.:

AF XY:

0.00859

AC XY:

638

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.00231

AC:

AN:

41554

American (AMR)

AF:

0.0132

AC:

197

AN:

14978

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00539

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0147

AC:

997

AN:

68022

Other (OTH)

AF:

0.00995

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0124

Hom.:

Bravo

AF:

0.00879

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BP4, BS1, BS2 -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 20, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 04, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA1H-related disorder

Benign:1

Apr 26, 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

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

-0.80

CADD

Benign

2.7

(source)

DANN

Benign

0.32

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000071

dbscSNV1_RF

Benign

0.0

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