rs2407083

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021098.3(CACNA1H):c.1668C>T(p.Pro556Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,546,556 control chromosomes in the GnomAD database, including 13,598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 982 hom., cov: 34)

Exomes 𝑓: 0.13 ( 12616 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.57

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 16-1202118-C-T is Benign according to our data. Variant chr16-1202118-C-T is described in ClinVar as Benign. ClinVar VariationId is 96002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.57 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.1668C>T	p.Pro556Pro	synonymous	Exon 9 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.1668C>T	p.Pro556Pro	synonymous	Exon 9 of 34	NP_001005407.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.1668C>T	p.Pro556Pro	synonymous	Exon 9 of 35	ENSP00000334198.7
CACNA1H	ENST00000569107.6	TSL:1	c.1668C>T	p.Pro556Pro	synonymous	Exon 9 of 34	ENSP00000454990.2
CACNA1H	ENST00000711493.1		c.1668C>T	p.Pro556Pro	synonymous	Exon 9 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15373

AN:

152178

Hom.:

980

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0376

Gnomad AMI

AF:

0.0749

Gnomad AMR

AF:

0.0847

Gnomad ASJ

AF:

0.0625

Gnomad EAS

AF:

0.0633

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.111

GnomAD2 exomes

AF:

0.115

AC:

16038

AN:

140046

AF XY:

0.121

show subpopulations

Gnomad AFR exome

AF:

0.0348

Gnomad AMR exome

AF:

0.0587

Gnomad ASJ exome

AF:

0.0739

Gnomad EAS exome

AF:

0.0691

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.135

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.131

AC:

182907

AN:

1394260

Hom.:

12616

Cov.:

AF XY:

0.132

AC XY:

91019

AN XY:

687576

show subpopulations

African (AFR)

AF:

0.0335

AC:

1055

AN:

31528

American (AMR)

AF:

0.0619

AC:

2204

AN:

35630

Ashkenazi Jewish (ASJ)

AF:

0.0733

AC:

1840

AN:

25106

East Asian (EAS)

AF:

0.0422

AC:

1505

AN:

35668

South Asian (SAS)

AF:

0.157

AC:

12445

AN:

79166

European-Finnish (FIN)

AF:

0.152

AC:

6982

AN:

45878

Middle Eastern (MID)

AF:

0.0949

AC:

540

AN:

5690

European-Non Finnish (NFE)

AF:

0.139

AC:

149473

AN:

1077734

Other (OTH)

AF:

0.119

AC:

6863

AN:

57860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

11023

22046

33070

44093

55116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5422

10844

16266

21688

27110

<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:

0.101

AC:

15369

AN:

152296

Hom.:

982

Cov.:

AF XY:

0.103

AC XY:

7634

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0375

AC:

1561

AN:

41584

American (AMR)

AF:

0.0846

AC:

1294

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0625

AC:

217

AN:

3470

East Asian (EAS)

AF:

0.0629

AC:

325

AN:

5166

South Asian (SAS)

AF:

0.156

AC:

755

AN:

4828

European-Finnish (FIN)

AF:

0.157

AC:

1665

AN:

10618

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.136

AC:

9222

AN:

68008

Other (OTH)

AF:

0.110

AC:

233

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

731

1462

2192

2923

3654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<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:

0.120

Hom.:

383

Bravo

AF:

0.0918

Asia WGS

AF:

0.111

AC:

388

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.62

(source)

DANN

Benign

0.80

PhyloP100

-2.6

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over