16-1208033-G-T

Variant names:

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.3175G>T(p.Ala1059Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00933 in 1,606,222 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1059A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 94 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.90

Publications

10 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=0.007585913).

BP6

Variant 16-1208033-G-T is Benign according to our data. Variant chr16-1208033-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00705 (1073/152182) while in subpopulation AMR AF = 0.0112 (172/15292). AF 95% confidence interval is 0.00987. There are 7 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1073 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.3136G>T	p.Ala1046Ser	missense_variant	Exon 16 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.3136G>T	p.Ala1046Ser	missense_variant	Exon 16 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3175G>T	p.Ala1059Ser	missense_variant	Exon 16 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*1088G>T		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2622G>T		non_coding_transcript_exon_variant	Exon 15 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3175G>T		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1088G>T		3_prime_UTR_variant	Exon 16 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2622G>T		3_prime_UTR_variant	Exon 15 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00707

AC:

1075

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00725

AC:

1707

AN:

235422

AF XY:

0.00757

show subpopulations

Gnomad AFR exome

AF:

0.00206

Gnomad AMR exome

AF:

0.00636

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.00957

AC:

13920

AN:

1454040

Hom.:

Cov.:

AF XY:

0.00945

AC XY:

6827

AN XY:

722570

show subpopulations

African (AFR)

AF:

0.00294

AC:

AN:

33340

American (AMR)

AF:

0.00660

AC:

290

AN:

43966

Ashkenazi Jewish (ASJ)

AF:

0.0157

AC:

409

AN:

25982

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39346

South Asian (SAS)

AF:

0.00394

AC:

334

AN:

84676

European-Finnish (FIN)

AF:

0.000928

AC:

AN:

51744

Middle Eastern (MID)

AF:

0.0398

AC:

225

AN:

5652

European-Non Finnish (NFE)

AF:

0.0107

AC:

11861

AN:

1109220

Other (OTH)

AF:

0.0109

AC:

654

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

718

1435

2153

2870

3588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.00705

AC:

1073

AN:

152182

Hom.:

Cov.:

AF XY:

0.00665

AC XY:

495

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41500

American (AMR)

AF:

0.0112

AC:

172

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0208

AC:

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00373

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0100

AC:

682

AN:

67998

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00923

Hom.:

Bravo

AF:

0.00753

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00247

AC:

ESP6500EA

AF:

0.0100

AC:

ExAC

AF:

0.00649

AC:

783

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Jun 03, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17696120, 25525159, 26706850)

Jun 06, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Benign:1

Jan 28, 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

Benign

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-0.042

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.76

T;T;T;.

MetaRNN

Benign

0.0076

T;T;T;T

MetaSVM

Uncertain

-0.053

MutationAssessor

Benign

1.8

L;.;L;L

PhyloP100

4.9

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.0

N;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.56

T;.;T;T

Sift4G

Benign

0.66

T;.;T;T

Vest4

0.47

ClinPred

0.022

GERP RS

3.0

Varity_R

0.081

gMVP

0.38

Mutation Taster

=100/0

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