NM_021098.3:c.300-8G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_021098.3(CACNA1H):c.300-8G>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 0.000234 in 1,604,724 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.0001985

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.15

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 -10 ACMG points.

BP6

Variant 16-1194964-G-A is Benign according to our data. Variant chr16-1194964-G-A is described in ClinVar as Benign. ClinVar VariationId is 767495.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000204 (31/152238) while in subpopulation EAS AF = 0.00562 (29/5156). AF 95% confidence interval is 0.00402. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.300-8G>A		splice_region_variant, intron_variant	Intron 2 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.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.300-8G>A	splice_region_variant, intron_variant	Intron 2 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00561

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000473

AC:

117

AN:

247178

AF XY:

0.000423

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00596

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000539

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000237

AC:

344

AN:

1452486

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

157

AN XY:

723032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00673

AC:

267

AN:

39656

South Asian (SAS)

AF:

0.000151

AC:

AN:

86098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52050

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000453

AC:

AN:

1104782

Other (OTH)

AF:

0.000200

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000204

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41542

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00562

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.000121

Hom.:

Bravo

AF:

0.000253

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Dec 08, 2024

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

-0.96

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.79

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