16-1207092-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.2881C>T(p.Leu961Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00779 in 1,598,686 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 7 hom., cov: 30)

Exomes 𝑓: 0.0080 ( 60 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.91

Publications

3 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: Labcorp Genetics (formerly Invitae), G2P
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNA1H links:

ENSG00000261294 (HGNC:):

ENSG00000261294 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 16-1207092-C-T is Benign according to our data. Variant chr16-1207092-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460073.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 = 0.00588 (894/152144) while in subpopulation NFE AF = 0.0105 (711/67968). AF 95% confidence interval is 0.00982. There are 7 homozygotes in GnomAd4. There are 412 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 894 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.2881C>T	p.Leu961Leu	synonymous	Exon 13 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.2881C>T	p.Leu961Leu	synonymous	Exon 13 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.2881C>T	p.Leu961Leu	synonymous	Exon 13 of 35	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6	TSL:1	c.2881C>T	p.Leu961Leu	synonymous	Exon 13 of 34	ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1		c.2881C>T	p.Leu961Leu	synonymous	Exon 13 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes

AF:

0.00588

AC:

894

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00475

AC:

1067

AN:

224732

AF XY:

0.00494

show subpopulations

Gnomad AFR exome

AF:

0.00128

Gnomad AMR exome

AF:

0.00292

Gnomad ASJ exome

AF:

0.000732

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00360

Gnomad NFE exome

AF:

0.00808

Gnomad OTH exome

AF:

0.00495

GnomAD4 exome

AF:

0.00799

AC:

11560

AN:

1446542

Hom.:

Cov.:

AF XY:

0.00797

AC XY:

5720

AN XY:

717994

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33236

American (AMR)

AF:

0.00289

AC:

124

AN:

42836

Ashkenazi Jewish (ASJ)

AF:

0.000967

AC:

AN:

25860

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39038

South Asian (SAS)

AF:

0.00178

AC:

149

AN:

83766

European-Finnish (FIN)

AF:

0.00354

AC:

183

AN:

51712

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00966

AC:

10671

AN:

1104526

Other (OTH)

AF:

0.00595

AC:

356

AN:

59816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

527

1053

1580

2106

2633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.00588

AC:

894

AN:

152144

Hom.:

Cov.:

AF XY:

0.00554

AC XY:

412

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

41486

American (AMR)

AF:

0.00510

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00166

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

711

AN:

67968

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

174

217

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:

0.00817

Hom.:

Bravo

AF:

0.00535

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CACNA1H-related disorder (1)

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV (1)

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

4.9

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over