rs59052554

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.2759C>G(p.Thr920Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000703 in 1,422,236 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T920M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89

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: 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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.2720C>G	p.Thr907Arg	missense_variant	Exon 12 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.2720C>G	p.Thr907Arg	missense_variant	Exon 12 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2759C>G	p.Thr920Arg	missense_variant	Exon 12 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*672C>G		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2206C>G		non_coding_transcript_exon_variant	Exon 11 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2759C>G		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*672C>G		3_prime_UTR_variant	Exon 12 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2206C>G		3_prime_UTR_variant	Exon 11 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1422236

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703774

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32432

American (AMR)

AF:

0.00

AC:

AN:

39608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25440

East Asian (EAS)

AF:

0.00

AC:

AN:

37608

South Asian (SAS)

AF:

0.00

AC:

AN:

80718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4406

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1093142

Other (OTH)

AF:

0.00

AC:

AN:

58880

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Feb 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;.;.;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.92

D;D;D;.

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Benign

0.90

L;.;L;L

PhyloP100

3.9

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.40

N;.;N;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0050

D;.;D;D

Sift4G

Uncertain

0.012

D;.;D;D

Polyphen

0.58

P;.;P;P

Vest4

0.57

MutPred

0.87

Gain of MoRF binding (P = 0.0872);.;Gain of MoRF binding (P = 0.0872);Gain of MoRF binding (P = 0.0872);

MVP

0.91

ClinPred

0.62

GERP RS

2.9

Varity_R

0.35

gMVP

0.94

Mutation Taster

=90/10

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over