rs543267343

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3155-4G>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 0.000065 in 1,598,972 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.00001810

Clinical Significance

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

Conservation

PhyloP100: -0.460

Publications

0 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=-0.86).

BP6

Variant 16-1208009-G-A is Benign according to our data. Variant chr16-1208009-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 460079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000854 (13/152224) while in subpopulation AMR AF = 0.000588 (9/15302). AF 95% confidence interval is 0.000306. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3155-4G>A		splice_region_variant, intron_variant	Intron 15 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.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3116-4G>A	splice_region_variant, intron_variant	Intron 15 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3116-4G>A	splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1068-4G>A	splice_region_variant, intron_variant	Intron 15 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2602-4G>A	splice_region_variant, intron_variant	Intron 14 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3155-4G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000932

AC:

AN:

225370

AF XY:

0.000131

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000186

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000500

Gnomad NFE exome

AF:

0.0000696

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000629

AC:

AN:

1446748

Hom.:

Cov.:

AF XY:

0.0000696

AC XY:

AN XY:

718302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33164

American (AMR)

AF:

0.000233

AC:

AN:

42888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25838

East Asian (EAS)

AF:

0.00

AC:

AN:

38888

South Asian (SAS)

AF:

0.000323

AC:

AN:

83580

European-Finnish (FIN)

AF:

0.0000195

AC:

AN:

51310

Middle Eastern (MID)

AF:

0.000354

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.0000398

AC:

AN:

1105570

Other (OTH)

AF:

0.000117

AC:

AN:

59854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

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:

0.0000854

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41522

American (AMR)

AF:

0.000588

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.00

Hom.:

Bravo

AF:

0.000125

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Mar 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA1H-related disorder

Benign:1

Jun 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.2

(source)

DANN

Benign

0.49

PhyloP100

-0.46

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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