16-1208189-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_021098.3(CACNA1H):c.3331G>A(p.Gly1111Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,550,434 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1111G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0052 ( 9 hom., cov: 33)

Exomes 𝑓: 0.00064 ( 7 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: -0.331

Publications

5 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005903363).

BP6

Variant 16-1208189-G-A is Benign according to our data. Variant chr16-1208189-G-A is described in ClinVar as Benign. ClinVar VariationId is 460084.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00522 (794/152146) while in subpopulation AFR AF = 0.0174 (721/41522). AF 95% confidence interval is 0.0163. There are 9 homozygotes in GnomAd4. There are 343 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 794 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 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.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3292G>A	p.Gly1098Arg	missense_variant	Exon 16 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3292G>A	p.Gly1098Arg	missense_variant	Exon 16 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3331G>A	p.Gly1111Arg	missense_variant	Exon 16 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1244G>A		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2778G>A		non_coding_transcript_exon_variant	Exon 15 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3331G>A		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1244G>A		3_prime_UTR_variant	Exon 16 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2778G>A		3_prime_UTR_variant	Exon 15 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00518

AC:

788

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0173

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00576

GnomAD2 exomes

AF:

0.00132

AC:

199

AN:

151142

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.0189

Gnomad AMR exome

AF:

0.00183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000893

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.00160

GnomAD4 exome

AF:

0.000644

AC:

901

AN:

1398288

Hom.:

Cov.:

AF XY:

0.000562

AC XY:

388

AN XY:

690700

show subpopulations

African (AFR)

AF:

0.0193

AC:

611

AN:

31642

American (AMR)

AF:

0.00221

AC:

AN:

36280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25210

East Asian (EAS)

AF:

0.0000278

AC:

AN:

35952

South Asian (SAS)

AF:

0.0000502

AC:

AN:

79624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45438

Middle Eastern (MID)

AF:

0.00231

AC:

AN:

4320

European-Non Finnish (NFE)

AF:

0.0000906

AC:

AN:

1081814

Other (OTH)

AF:

0.00167

AC:

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00522

AC:

794

AN:

152146

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

343

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0174

AC:

721

AN:

41522

American (AMR)

AF:

0.00308

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67984

Other (OTH)

AF:

0.00570

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

116

154

193

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:

0.000637

Hom.:

Bravo

AF:

0.00639

ESP6500AA

AF:

0.00780

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000602

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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

0.16

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

8.9

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.091

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.75

T;T;T;.

MetaRNN

Benign

0.0059

T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.0

N;.;N;N

PhyloP100

-0.33

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.23

N;.;N;N

REVEL

Benign

0.19

Sift

Benign

0.35

T;.;T;T

Sift4G

Benign

0.51

T;.;T;T

Polyphen

0.58

P;.;P;P

Vest4

0.21

MutPred

0.28

Gain of solvent accessibility (P = 0.019);.;Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);

MVP

0.61

ClinPred

0.0061

GERP RS

-1.8

Varity_R

0.063

gMVP

0.44

Mutation Taster

=100/0

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