rs59027578

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(CACNA1H):c.4929+8C>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 0.0000106 in 1,607,200 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.000008109

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.724

Publications

4 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 16-1213939-C-A is Benign according to our data. Variant chr16-1213939-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 807342.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000046 (7/152272) while in subpopulation EAS AF = 0.00136 (7/5146). AF 95% confidence interval is 0.000638. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4929+8C>A		splice_region_variant, intron_variant	Intron 27 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4944+8C>A	splice_region_variant, intron_variant	Intron 26 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4947+8C>A	splice_region_variant, intron_variant	Intron 26 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4911+8C>A	splice_region_variant, intron_variant	Intron 26 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.4944+8C>A	splice_region_variant, intron_variant	Intron 27 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4890+8C>A	splice_region_variant, intron_variant	Intron 27 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4911+8C>A	splice_region_variant, intron_variant	Intron 26 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4872+8C>A	splice_region_variant, intron_variant	Intron 26 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4911+8C>A	splice_region_variant, intron_variant	Intron 26 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*881+8C>A	splice_region_variant, intron_variant	Intron 26 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*10+8C>A	splice_region_variant, intron_variant	Intron 27 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*2780+8C>A	splice_region_variant, intron_variant	Intron 27 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*4373+8C>A	splice_region_variant, intron_variant	Intron 25 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4911+8C>A	splice_region_variant, intron_variant	Intron 26 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4911+8C>A	splice_region_variant, intron_variant	Intron 26 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.5006+8C>A	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4911+8C>A	splice_region_variant, intron_variant	Intron 26 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4929+8C>A	splice_region_variant, intron_variant	Intron 27 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4988+8C>A	splice_region_variant, intron_variant	Intron 26 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152154

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:

0.00136

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000339

AC:

AN:

236234

AF XY:

0.0000156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000462

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000687

AC:

AN:

1454928

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25968

East Asian (EAS)

AF:

0.000203

AC:

AN:

39464

South Asian (SAS)

AF:

0.00

AC:

AN:

85004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109670

Other (OTH)

AF:

0.0000333

AC:

AN:

60084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.0000460

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00136

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Jan 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jun 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jun 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

0.47

(source)

DANN

Benign

0.37

PhyloP100

-0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000081

dbscSNV1_RF

Benign

0.032

SpliceAI score (max)

0.010

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