16-1218013-G-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.5418G>C(p.Thr1806Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 1,600,998 control chromosomes in the GnomAD database, including 3,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1806T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.047 ( 248 hom., cov: 34)

Exomes 𝑓: 0.061 ( 3054 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -7.87

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

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=-0.84).

BP6

Variant 16-1218013-G-C is Benign according to our data. Variant chr16-1218013-G-C is described in ClinVar as Benign. ClinVar VariationId is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-7.86 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

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.5418G>C	p.Thr1806Thr	synonymous	Exon 32 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.5400G>C	p.Thr1800Thr	synonymous	Exon 31 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.5418G>C	p.Thr1806Thr	synonymous	Exon 32 of 35	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6	TSL:1	c.5433G>C	p.Thr1811Thr	synonymous	Exon 31 of 34	ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1		c.5436G>C	p.Thr1812Thr	synonymous	Exon 31 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes

AF:

0.0470

AC:

7150

AN:

152194

Hom.:

247

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00941

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.0438

Gnomad ASJ

AF:

0.0911

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0786

Gnomad FIN

AF:

0.0489

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0672

Gnomad OTH

AF:

0.0587

GnomAD2 exomes

AF:

0.0546

AC:

12461

AN:

228046

AF XY:

0.0587

show subpopulations

Gnomad AFR exome

AF:

0.00869

Gnomad AMR exome

AF:

0.0311

Gnomad ASJ exome

AF:

0.0917

Gnomad EAS exome

AF:

0.000238

Gnomad FIN exome

AF:

0.0493

Gnomad NFE exome

AF:

0.0653

Gnomad OTH exome

AF:

0.0676

GnomAD4 exome

AF:

0.0606

AC:

87838

AN:

1448686

Hom.:

3054

Cov.:

AF XY:

0.0618

AC XY:

44455

AN XY:

719566

show subpopulations

African (AFR)

AF:

0.00848

AC:

282

AN:

33244

American (AMR)

AF:

0.0321

AC:

1394

AN:

43368

Ashkenazi Jewish (ASJ)

AF:

0.0936

AC:

2419

AN:

25848

East Asian (EAS)

AF:

0.000205

AC:

AN:

39080

South Asian (SAS)

AF:

0.0845

AC:

7122

AN:

84258

European-Finnish (FIN)

AF:

0.0512

AC:

2617

AN:

51140

Middle Eastern (MID)

AF:

0.0844

AC:

485

AN:

5748

European-Non Finnish (NFE)

AF:

0.0632

AC:

69867

AN:

1106164

Other (OTH)

AF:

0.0609

AC:

3644

AN:

59836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4804

9608

14412

19216

24020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2484

4968

7452

9936

12420

<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:

0.0470

AC:

7152

AN:

152312

Hom.:

248

Cov.:

AF XY:

0.0455

AC XY:

3390

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00938

AC:

390

AN:

41580

American (AMR)

AF:

0.0438

AC:

670

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0911

AC:

316

AN:

3468

East Asian (EAS)

AF:

0.00135

AC:

AN:

5178

South Asian (SAS)

AF:

0.0793

AC:

382

AN:

4820

European-Finnish (FIN)

AF:

0.0489

AC:

519

AN:

10620

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0672

AC:

4569

AN:

68014

Other (OTH)

AF:

0.0577

AC:

122

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

373

747

1120

1494

1867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0547

Hom.:

Bravo

AF:

0.0421

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.32

(source)

DANN

Benign

0.75

PhyloP100

-7.9

Mutation Taster

=78/22

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over