rs770983743

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PP3_ModerateBP6_Moderate

The NM_021098.3(CACNA1H):c.1172A>G(p.His391Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,402,790 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H391Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 9.06

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:

LOC124903623 (HGNC:):

LOC124903623 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

BP6

Variant 16-1200768-A-G is Benign according to our data. Variant chr16-1200768-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 573006.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 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.1172A>G	p.His391Arg	missense_variant	Exon 8 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1133A>G	p.His378Arg	missense_variant	Exon 8 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1133A>G	p.His378Arg	missense_variant	Exon 8 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.1172A>G	p.His391Arg	missense_variant	Exon 8 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*619A>G		non_coding_transcript_exon_variant	Exon 7 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.1172A>G		non_coding_transcript_exon_variant	Exon 8 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*619A>G		3_prime_UTR_variant	Exon 7 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000620

AC:

AN:

161198

AF XY:

0.0000117

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000285

AC:

AN:

1402790

Hom.:

Cov.:

AF XY:

0.00000433

AC XY:

AN XY:

692270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31714

American (AMR)

AF:

0.00

AC:

AN:

36082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25230

East Asian (EAS)

AF:

0.00

AC:

AN:

36002

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1081140

Other (OTH)

AF:

0.0000172

AC:

AN:

58226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000916

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Dec 02, 2022

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

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

D;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D;D;.

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;.;L;L

PhyloP100

9.1

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.3

D;.;D;D

REVEL

Pathogenic

0.72

Sift

Benign

0.045

D;.;D;D

Sift4G

Uncertain

0.0020

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.74

MutPred

0.37

Gain of relative solvent accessibility (P = 0.1259);.;Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);

MVP

0.97

ClinPred

0.98

GERP RS

3.9

Varity_R

0.77

gMVP

0.95

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs770983743

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