rs759233103

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021098.3(CACNA1H):c.4244G>A(p.Gly1415Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G1415G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.77

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4205G>A	p.Gly1402Asp	missense_variant	Exon 22 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4205G>A	p.Gly1402Asp	missense_variant	Exon 22 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4244G>A	p.Gly1415Asp	missense_variant	Exon 22 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*214G>A		non_coding_transcript_exon_variant	Exon 22 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2157G>A		non_coding_transcript_exon_variant	Exon 22 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3691G>A		non_coding_transcript_exon_variant	Exon 21 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4244G>A		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*214G>A		3_prime_UTR_variant	Exon 22 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2157G>A		3_prime_UTR_variant	Exon 22 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3691G>A		3_prime_UTR_variant	Exon 21 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248088

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460574

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726552

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111730

Other (OTH)

AF:

0.00

AC:

AN:

60354

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

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

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (rs759233103, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1415 of the CACNA1H protein (p.Gly1415Asp). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1H protein function. ClinVar contains an entry for this variant (Variation ID: 576471). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;.;H;H

PhyloP100

9.8

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.7

D;.;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.68

MutPred

0.68

Loss of methylation at R1412 (P = 0.058);.;Loss of methylation at R1412 (P = 0.058);Loss of methylation at R1412 (P = 0.058);

MVP

0.96

ClinPred

1.0

GERP RS

4.3

Varity_R

0.95

gMVP

0.94

Mutation Taster

=19/81

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over