chr16-1206259-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.2759C>T(p.Thr920Met) variant causes a missense change. The variant allele was found at a frequency of 0.00259 in 1,574,574 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. T920R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 9 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.89

Publications

6 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=0.010669082).

BP6

Variant 16-1206259-C-T is Benign according to our data. Variant chr16-1206259-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376802.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 = 0.0016 (244/152340) while in subpopulation NFE AF = 0.00241 (164/68024). AF 95% confidence interval is 0.00211. There are 2 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.2720C>T	p.Thr907Met	missense_variant	Exon 12 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.2720C>T	p.Thr907Met	missense_variant	Exon 12 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2759C>T	p.Thr920Met	missense_variant	Exon 12 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*672C>T		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2206C>T		non_coding_transcript_exon_variant	Exon 11 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2759C>T		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*672C>T		3_prime_UTR_variant	Exon 12 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2206C>T		3_prime_UTR_variant	Exon 11 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00225

AC:

429

AN:

190264

AF XY:

0.00222

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00380

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000445

Gnomad NFE exome

AF:

0.00345

Gnomad OTH exome

AF:

0.00316

GnomAD4 exome

AF:

0.00269

AC:

3832

AN:

1422234

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

1840

AN XY:

703772

show subpopulations

African (AFR)

AF:

0.000740

AC:

AN:

32432

American (AMR)

AF:

0.00109

AC:

AN:

39608

Ashkenazi Jewish (ASJ)

AF:

0.00358

AC:

AN:

25440

East Asian (EAS)

AF:

0.000106

AC:

AN:

37608

South Asian (SAS)

AF:

0.00168

AC:

136

AN:

80718

European-Finnish (FIN)

AF:

0.000480

AC:

AN:

50000

Middle Eastern (MID)

AF:

0.00113

AC:

AN:

4406

European-Non Finnish (NFE)

AF:

0.00308

AC:

3365

AN:

1093142

Other (OTH)

AF:

0.00238

AC:

140

AN:

58880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

231

463

694

926

1157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00160

AC:

244

AN:

152340

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41578

American (AMR)

AF:

0.000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00241

AC:

164

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.177

Hom.:

6952

Bravo

AF:

0.00168

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000947

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00228

AC:

266

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1, BS2 -

Dec 02, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Benign:1

Jan 03, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: BS1, BP1, BP4 -

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

Benign:1

Jan 27, 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

0.028

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.36

T;.;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.86

D;D;D;.

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Uncertain

-0.067

MutationAssessor

Benign

-1.8

N;.;N;N

PhyloP100

3.9

PrimateAI

Benign

0.45

PROVEAN

Benign

5.0

N;.;N;N

REVEL

Benign

0.28

Sift

Benign

1.0

T;.;T;T

Sift4G

Benign

1.0

T;.;T;T

Polyphen

0.0060

B;.;B;B

Vest4

0.29

MVP

0.43

ClinPred

0.0041

GERP RS

2.9

Varity_R

0.038

gMVP

0.66

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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