rs201352768

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.3925G>A(p.Val1309Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000549 in 1,611,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. V1309F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00057 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.33

Publications

4 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030431986).

BP6

Variant 16-1210449-G-A is Benign according to our data. Variant chr16-1210449-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 570660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000343 (52/151532) while in subpopulation NFE AF = 0.000633 (43/67910). AF 95% confidence interval is 0.000482. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 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.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3886G>A	p.Val1296Ile	missense_variant	Exon 19 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3886G>A	p.Val1296Ile	missense_variant	Exon 19 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3925G>A	p.Val1309Ile	missense_variant	Exon 19 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3975G>A		non_coding_transcript_exon_variant	Exon 19 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1838G>A		non_coding_transcript_exon_variant	Exon 19 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3372G>A		non_coding_transcript_exon_variant	Exon 18 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3925G>A		non_coding_transcript_exon_variant	Exon 19 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1838G>A		3_prime_UTR_variant	Exon 19 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3372G>A		3_prime_UTR_variant	Exon 18 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000343

AC:

AN:

151532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000286

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000633

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000461

AC:

114

AN:

247246

AF XY:

0.000490

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000804

Gnomad NFE exome

AF:

0.000805

Gnomad OTH exome

AF:

0.000833

GnomAD4 exome

AF:

0.000571

AC:

833

AN:

1459848

Hom.:

Cov.:

AF XY:

0.000580

AC XY:

421

AN XY:

726260

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33466

American (AMR)

AF:

0.0000672

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.000886

AC:

AN:

51916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000683

AC:

759

AN:

1111662

Other (OTH)

AF:

0.000315

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.000343

AC:

AN:

151532

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

AN XY:

73908

show subpopulations

African (AFR)

AF:

0.0000485

AC:

AN:

41220

American (AMR)

AF:

0.0000658

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.000286

AC:

AN:

10496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000633

AC:

AN:

67910

Other (OTH)

AF:

0.00144

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000435

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000421

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

CACNA1H-related disorder

Benign:1

May 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Dec 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Nov 23, 2024

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

Benign

0.054

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.39

T;.;.;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.83

T;T;T;.

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.030

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

-2.6

N;.;N;N

PhyloP100

4.3

PrimateAI

Benign

0.44

PROVEAN

Benign

0.84

N;.;N;N

REVEL

Uncertain

0.30

Sift

Benign

1.0

T;.;T;T

Sift4G

Benign

1.0

T;.;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.12

MVP

0.53

ClinPred

0.012

GERP RS

2.7

PromoterAI

-0.21

Neutral

(source)

Varity_R

0.052

gMVP

0.31

Mutation Taster

=88/12

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