rs8063574

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.3957T>C(p.Asp1319Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 1,611,656 control chromosomes in the GnomAD database, including 552,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 55890 hom., cov: 30)

Exomes 𝑓: 0.82 ( 496674 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.43

Publications

24 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=-0.78).

BP6

Variant 16-1210481-T-C is Benign according to our data. Variant chr16-1210481-T-C is described in ClinVar as Benign. ClinVar VariationId is 96011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3957T>C	p.Asp1319Asp	synonymous_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.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3918T>C	p.Asp1306Asp	synonymous_variant	Exon 19 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3918T>C	p.Asp1306Asp	synonymous_variant	Exon 19 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3957T>C	p.Asp1319Asp	synonymous_variant	Exon 19 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.4007T>C		non_coding_transcript_exon_variant	Exon 19 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1870T>C		non_coding_transcript_exon_variant	Exon 19 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3404T>C		non_coding_transcript_exon_variant	Exon 18 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3957T>C		non_coding_transcript_exon_variant	Exon 19 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1870T>C		3_prime_UTR_variant	Exon 19 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3404T>C		3_prime_UTR_variant	Exon 18 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.856

AC:

129918

AN:

151858

Hom.:

55831

Cov.:

show subpopulations

Gnomad AFR

AF:

0.911

Gnomad AMI

AF:

0.798

Gnomad AMR

AF:

0.861

Gnomad ASJ

AF:

0.886

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.946

Gnomad FIN

AF:

0.860

Gnomad MID

AF:

0.905

Gnomad NFE

AF:

0.801

Gnomad OTH

AF:

0.864

GnomAD2 exomes

AF:

0.860

AC:

212401

AN:

246952

AF XY:

0.861

show subpopulations

Gnomad AFR exome

AF:

0.911

Gnomad AMR exome

AF:

0.872

Gnomad ASJ exome

AF:

0.878

Gnomad EAS exome

AF:

0.999

Gnomad FIN exome

AF:

0.854

Gnomad NFE exome

AF:

0.805

Gnomad OTH exome

AF:

0.849

GnomAD4 exome

AF:

0.823

AC:

1201671

AN:

1459682

Hom.:

496674

Cov.:

AF XY:

0.826

AC XY:

599791

AN XY:

726178

show subpopulations

African (AFR)

AF:

0.919

AC:

30759

AN:

33472

American (AMR)

AF:

0.868

AC:

38804

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.879

AC:

22959

AN:

26130

East Asian (EAS)

AF:

0.999

AC:

39663

AN:

39694

South Asian (SAS)

AF:

0.937

AC:

80840

AN:

86242

European-Finnish (FIN)

AF:

0.852

AC:

44088

AN:

51718

Middle Eastern (MID)

AF:

0.902

AC:

5204

AN:

5768

European-Non Finnish (NFE)

AF:

0.799

AC:

888425

AN:

1111628

Other (OTH)

AF:

0.844

AC:

50929

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

12220

24440

36660

48880

61100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20844

41688

62532

83376

104220

<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:

0.856

AC:

130035

AN:

151974

Hom.:

55890

Cov.:

AF XY:

0.861

AC XY:

63912

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.911

AC:

37787

AN:

41478

American (AMR)

AF:

0.861

AC:

13138

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.886

AC:

3071

AN:

3468

East Asian (EAS)

AF:

0.999

AC:

5135

AN:

5140

South Asian (SAS)

AF:

0.945

AC:

4549

AN:

4812

European-Finnish (FIN)

AF:

0.860

AC:

9115

AN:

10594

Middle Eastern (MID)

AF:

0.901

AC:

265

AN:

294

European-Non Finnish (NFE)

AF:

0.801

AC:

54420

AN:

67914

Other (OTH)

AF:

0.867

AC:

1829

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

965

1930

2895

3860

4825

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

890

1780

2670

3560

4450

<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:

0.828

Hom.:

101047

Bravo

AF:

0.857

EpiCase

AF:

0.814

EpiControl

AF:

0.807

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Epilepsy, childhood absence, susceptibility to, 6

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 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

Uncertain

0.53

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.3

(source)

DANN

Benign

0.62

PhyloP100

-1.4

PromoterAI

0.0067

Neutral

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over