rs376566207

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_021098.3(CACNA1H):c.552G>A(p.Met184Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,612,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.66

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_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3480633).

BP6

Variant 16-1195932-G-A is Benign according to our data. Variant chr16-1195932-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568589.

BS2

High AC in GnomAdExome4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.513G>A	p.Met171Ile	missense_variant	Exon 5 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.513G>A	p.Met171Ile	missense_variant	Exon 5 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.552G>A	p.Met184Ile	missense_variant	Exon 5 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711448.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 5 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*90+273G>A		intron_variant	Intron 4 of 33			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248280

AF XY:

0.0000222

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:

0.0000178

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1460588

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726616

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1111642

Other (OTH)

AF:

0.0000166

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.427

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:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

T;.;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.015

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D;.

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.35

T;T;T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

-0.17

N;.;N;N

PhyloP100

5.7

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.66

N;.;N;N

REVEL

Uncertain

0.54

Sift

Benign

0.16

T;.;T;T

Sift4G

Benign

0.080

T;.;T;T

Polyphen

0.24

B;.;B;B

Vest4

0.80

MutPred

0.52

Gain of catalytic residue at M184 (P = 0.0031);.;Gain of catalytic residue at M184 (P = 0.0031);Gain of catalytic residue at M184 (P = 0.0031);

MVP

0.86

ClinPred

0.40

GERP RS

4.2

Varity_R

0.23

gMVP

0.62

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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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