ENST00000569107.6:c.4760G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000569107.6(CACNA1H):c.4760G>A(p.Ser1587Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1H
ENST00000569107.6 missense

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.58

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_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000569107.6 link	c.4760G>A	p.Ser1587Asn	missense_variant	Exon 25 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000348261.11 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000711493.1 link	c.4795+1G>A		splice_donor_variant, intron_variant	Intron 25 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4697+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4720+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4720+1G>A		splice_donor_variant, intron_variant	Intron 25 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*729+1G>A		splice_donor_variant, intron_variant	Intron 25 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4697+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2610+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4144+1G>A		splice_donor_variant, intron_variant	Intron 24 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4759+1G>A		splice_donor_variant, intron_variant	Intron 25 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000422

AC:

AN:

236870

AF XY:

0.00000770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000571

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450504

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33366

American (AMR)

AF:

0.00

AC:

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4710

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110444

Other (OTH)

AF:

0.00

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Mar 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CACNA1H cause disease. This variant has not been reported in the literature in individuals with CACNA1H-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 25 of the CACNA1H gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

PhyloP100

9.6

GERP RS

4.1

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: 32

DS_DL_spliceai

0.98

Position offset: -1

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over