chr16-1211282-T-C

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.4338T>C(p.Ile1446Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 1,612,988 control chromosomes in the GnomAD database, including 553,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.85 ( 55858 hom., cov: 34)

Exomes 𝑓: 0.82 ( 497524 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.120

Publications

26 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=-0.73).

BP6

Variant 16-1211282-T-C is Benign according to our data. Variant chr16-1211282-T-C is described in ClinVar as Benign. ClinVar VariationId is 585644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.12 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.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 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.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4299T>C	p.Ile1433Ile	synonymous_variant	Exon 22 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4299T>C	p.Ile1433Ile	synonymous_variant	Exon 22 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4338T>C	p.Ile1446Ile	synonymous_variant	Exon 22 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*308T>C		non_coding_transcript_exon_variant	Exon 22 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2251T>C		non_coding_transcript_exon_variant	Exon 22 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3785T>C		non_coding_transcript_exon_variant	Exon 21 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4338T>C		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*308T>C		3_prime_UTR_variant	Exon 22 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2251T>C		3_prime_UTR_variant	Exon 22 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3785T>C		3_prime_UTR_variant	Exon 21 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.854

AC:

130018

AN:

152160

Hom.:

55798

Cov.:

show subpopulations

Gnomad AFR

AF:

0.906

Gnomad AMI

AF:

0.797

Gnomad AMR

AF:

0.861

Gnomad ASJ

AF:

0.885

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.946

Gnomad FIN

AF:

0.860

Gnomad MID

AF:

0.905

Gnomad NFE

AF:

0.802

Gnomad OTH

AF:

0.864

GnomAD2 exomes

AF:

0.860

AC:

213791

AN:

248576

AF XY:

0.861

show subpopulations

Gnomad AFR exome

AF:

0.906

Gnomad AMR exome

AF:

0.872

Gnomad ASJ exome

AF:

0.879

Gnomad EAS exome

AF:

0.999

Gnomad FIN exome

AF:

0.852

Gnomad NFE exome

AF:

0.806

Gnomad OTH exome

AF:

0.849

GnomAD4 exome

AF:

0.824

AC:

1203161

AN:

1460710

Hom.:

497524

Cov.:

AF XY:

0.826

AC XY:

600478

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.915

AC:

30631

AN:

33474

American (AMR)

AF:

0.868

AC:

38822

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.879

AC:

22963

AN:

26132

East Asian (EAS)

AF:

0.999

AC:

39665

AN:

39694

South Asian (SAS)

AF:

0.938

AC:

80903

AN:

86254

European-Finnish (FIN)

AF:

0.852

AC:

44854

AN:

52646

Middle Eastern (MID)

AF:

0.902

AC:

5200

AN:

5766

European-Non Finnish (NFE)

AF:

0.800

AC:

889216

AN:

1111686

Other (OTH)

AF:

0.844

AC:

50907

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

12133

24266

36400

48533

60666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20848

41696

62544

83392

104240

<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:

0.855

AC:

130138

AN:

152278

Hom.:

55858

Cov.:

AF XY:

0.860

AC XY:

64011

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.907

AC:

37692

AN:

41574

American (AMR)

AF:

0.861

AC:

13174

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.885

AC:

3072

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5166

AN:

5172

South Asian (SAS)

AF:

0.946

AC:

4564

AN:

4826

European-Finnish (FIN)

AF:

0.860

AC:

9131

AN:

10612

Middle Eastern (MID)

AF:

0.901

AC:

265

AN:

294

European-Non Finnish (NFE)

AF:

0.802

AC:

54514

AN:

67996

Other (OTH)

AF:

0.866

AC:

1833

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

993

1986

2978

3971

4964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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.:

97269

Bravo

AF:

0.855

Asia WGS

AF:

0.969

AC:

3369

AN:

3478

EpiCase

AF:

0.815

EpiControl

AF:

0.808

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 16, 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

- -

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

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.4

(source)

DANN

Benign

0.54

PhyloP100

-0.12

Mutation Taster

=97/3

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