rs764360814

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_021098.3(CACNA1H):c.3154+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 0.000062 in 1,579,982 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.9963

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.13

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: Likely_benign. The variant received -3 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BS2

High AC in GnomAdExome4 at 97 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3154+5G>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.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3115+5G>A	splice_region_variant, intron_variant	Intron 15 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3115+5G>A	splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1067+5G>A	splice_region_variant, intron_variant	Intron 15 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2601+5G>A	splice_region_variant, intron_variant	Intron 14 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3154+5G>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000206

AC:

AN:

194446

AF XY:

0.0000287

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000110

Gnomad EAS exome

AF:

0.0000738

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000237

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000679

AC:

AN:

1427776

Hom.:

Cov.:

AF XY:

0.0000608

AC XY:

AN XY:

707668

show subpopulations

African (AFR)

AF:

0.0000920

AC:

AN:

32612

American (AMR)

AF:

0.00

AC:

AN:

39796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25604

East Asian (EAS)

AF:

0.0000797

AC:

AN:

37648

South Asian (SAS)

AF:

0.0000367

AC:

AN:

81742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50728

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000767

AC:

AN:

1094690

Other (OTH)

AF:

0.0000675

AC:

AN:

59218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000239

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Jan 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Aug 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 15 of the CACNA1H gene. It does not directly change the encoded amino acid sequence of the CACNA1H protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 958854). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

1.1

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.78

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: 8

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over