rs375121203

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_021098.3(CACNA1H):c.1144G>A(p.Asp382Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,560,986 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.71

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:

LOC124903623 (HGNC:):

LOC124903623 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

BP6

Variant 16-1200740-G-A is Benign according to our data. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077. Variant chr16-1200740-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568077.

BS2

High AC in GnomAdExome4 at 232 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1144G>A	p.Asp382Asn	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.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1105G>A	p.Asp369Asn	missense_variant	Exon 8 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1105G>A	p.Asp369Asn	missense_variant	Exon 8 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.1144G>A	p.Asp382Asn	missense_variant	Exon 8 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*591G>A		non_coding_transcript_exon_variant	Exon 7 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.1144G>A		non_coding_transcript_exon_variant	Exon 8 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*591G>A		3_prime_UTR_variant	Exon 7 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000651

AC:

AN:

169076

AF XY:

0.0000998

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000390

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.000213

GnomAD4 exome

AF:

0.000165

AC:

232

AN:

1408790

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

126

AN XY:

695948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31904

American (AMR)

AF:

0.0000273

AC:

AN:

36658

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25282

East Asian (EAS)

AF:

0.00

AC:

AN:

36428

South Asian (SAS)

AF:

0.00

AC:

AN:

80472

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.000205

AC:

222

AN:

1084666

Other (OTH)

AF:

0.000137

AC:

AN:

58432

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000823

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000605

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1144G>A (p.D382N) alteration is located in exon 8 (coding exon 7) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 1144, causing the aspartic acid (D) at amino acid position 382 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Jan 08, 2025

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

0.88

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D;.

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

L;.;L;L

PhyloP100

9.7

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.0

D;.;D;D

REVEL

Pathogenic

0.80

Sift

Benign

0.048

D;.;D;D

Sift4G

Uncertain

0.0020

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.80

MVP

0.95

ClinPred

0.70

GERP RS

3.9

Varity_R

0.57

gMVP

0.92

Mutation Taster

=60/40

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over