16-1218979-C-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.5897C>T(p.Ala1966Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,550,154 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 29 hom., cov: 31)

Exomes 𝑓: 0.022 ( 402 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.978

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=0.0041008294).

BP6

Variant 16-1218979-C-T is Benign according to our data. Variant chr16-1218979-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0153 (2328/152242) while in subpopulation SAS AF = 0.0271 (131/4834). AF 95% confidence interval is 0.0233. There are 29 homozygotes in GnomAd4. There are 1169 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 2328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5897C>T	p.Ala1966Val	missense_variant	Exon 34 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.5897C>T	p.Ala1966Val	missense_variant	Exon 34 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5912C>T	p.Ala1971Val	missense_variant	Exon 33 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000565831.7 link	c.5879C>T	p.Ala1960Val	missense_variant	Exon 33 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.5858C>T	p.Ala1953Val	missense_variant	Exon 34 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000711438.1 link	c.5840C>T	p.Ala1947Val	missense_variant	Exon 33 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5897C>T	p.Ala1966Val	missense_variant	Exon 34 of 36			ENSP00000518771.1
CACNA1H	ENST00000711483.1 link	c.5897C>T	p.Ala1966Val	missense_variant	Exon 34 of 35			ENSP00000518772.1
CACNA1H	ENST00000621827.2 link	n.5897C>T		non_coding_transcript_exon_variant	Exon 34 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000711442.1 link	n.*5341C>T		non_coding_transcript_exon_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711449.1 link	n.*756C>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711452.1 link	n.*564C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711486.1 link	n.5897C>T		non_coding_transcript_exon_variant	Exon 34 of 37			ENSP00000518775.1
CACNA1H	ENST00000711488.1 link	n.*1013C>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*5341C>T		3_prime_UTR_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711449.1 link	n.*756C>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711452.1 link	n.*564C>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711488.1 link	n.*1013C>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000711493.1 link	c.5906-24C>T		intron_variant	Intron 32 of 33			ENSP00000518778.1
CACNA1H	ENST00000711450.1 link	c.5903-24C>T		intron_variant	Intron 33 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5888-24C>T		intron_variant	Intron 33 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.6 link	c.5870-24C>T		intron_variant	Intron 32 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711485.1 link	c.5870-24C>T		intron_variant	Intron 32 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5888-69C>T		intron_variant	Intron 33 of 35			ENSP00000518768.1
CACNA1H	ENST00000711456.1 link	c.5887+328C>T		intron_variant	Intron 33 of 33			ENSP00000518769.1
CACNA1H	ENST00000637236.3 link	n.*1840-24C>T		intron_variant	Intron 32 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*969-24C>T		intron_variant	Intron 33 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3739-24C>T		intron_variant	Intron 33 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711448.1 link	n.*862-24C>T		intron_variant	Intron 34 of 35			ENSP00000518760.1
CACNA1H	ENST00000711451.1 link	n.*1500-24C>T		intron_variant	Intron 34 of 35			ENSP00000518763.1
CACNA1H	ENST00000711453.1 link	n.*555-24C>T		intron_variant	Intron 34 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5870-24C>T		intron_variant	Intron 32 of 34			ENSP00000518773.1
CACNA1H	ENST00000711487.1 link	n.5888-24C>T		intron_variant	Intron 33 of 35			ENSP00000518776.1

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2327

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00394

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0234

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0170

AC:

2628

AN:

154172

AF XY:

0.0176

show subpopulations

Gnomad AFR exome

AF:

0.00401

Gnomad AMR exome

AF:

0.00743

Gnomad ASJ exome

AF:

0.00768

Gnomad EAS exome

AF:

0.0000922

Gnomad FIN exome

AF:

0.0206

Gnomad NFE exome

AF:

0.0239

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0223

AC:

31200

AN:

1397912

Hom.:

402

Cov.:

AF XY:

0.0223

AC XY:

15400

AN XY:

689506

show subpopulations

African (AFR)

AF:

0.00298

AC:

AN:

31594

American (AMR)

AF:

0.00801

AC:

286

AN:

35690

Ashkenazi Jewish (ASJ)

AF:

0.00870

AC:

219

AN:

25164

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35734

South Asian (SAS)

AF:

0.0235

AC:

1858

AN:

79228

European-Finnish (FIN)

AF:

0.0207

AC:

995

AN:

48054

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.0246

AC:

26557

AN:

1078830

Other (OTH)

AF:

0.0195

AC:

1129

AN:

57982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1616

3231

4847

6462

8078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1006

2012

3018

4024

5030

<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:

0.0153

AC:

2328

AN:

152242

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1169

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00392

AC:

163

AN:

41540

American (AMR)

AF:

0.0108

AC:

165

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.0271

AC:

131

AN:

4834

European-Finnish (FIN)

AF:

0.0211

AC:

224

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0234

AC:

1593

AN:

68000

Other (OTH)

AF:

0.0123

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

109

217

326

434

543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0142

Hom.:

Bravo

AF:

0.0132

TwinsUK

AF:

0.0256

AC:

ALSPAC

AF:

0.0252

AC:

ESP6500AA

AF:

0.00475

AC:

ESP6500EA

AF:

0.0202

AC:

133

ExAC

AF:

0.0114

AC:

435

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 20, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Nov 04, 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

Feb 03, 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

0.086

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.082

T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.58

T;T;T;.

MetaRNN

Benign

0.0041

T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.90

L;.;.;.

PhyloP100

0.98

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.050

N;.;N;N

REVEL

Benign

0.29

Sift

Benign

0.30

T;.;T;T

Sift4G

Benign

0.51

T;.;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.045

ClinPred

0.00072

GERP RS

3.5

La Branchor

0.40

Varity_R

0.029

gMVP

0.19

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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