16-1205206-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_021098.3(CACNA1H):c.2544C>T(p.Gly848Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00986 in 1,613,002 control chromosomes in the GnomAD database, including 1,267 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. G848G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.051 ( 661 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 606 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.44

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 16-1205206-C-T is Benign according to our data. Variant chr16-1205206-C-T is described in ClinVar as Benign. ClinVar VariationId is 460066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.44 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 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.2544C>T	p.Gly848Gly	synonymous	Exon 11 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.2544C>T	p.Gly848Gly	synonymous	Exon 11 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.2544C>T	p.Gly848Gly	synonymous	Exon 11 of 35	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6	TSL:1	c.2544C>T	p.Gly848Gly	synonymous	Exon 11 of 34	ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1		c.2544C>T	p.Gly848Gly	synonymous	Exon 11 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes

AF:

0.0508

AC:

7733

AN:

152156

Hom.:

650

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0228

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.0363

GnomAD2 exomes

AF:

0.0133

AC:

3299

AN:

248584

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.180

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.000998

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000746

Gnomad OTH exome

AF:

0.00779

GnomAD4 exome

AF:

0.00557

AC:

8131

AN:

1460728

Hom.:

606

Cov.:

AF XY:

0.00486

AC XY:

3529

AN XY:

726638

show subpopulations

African (AFR)

AF:

0.181

AC:

6075

AN:

33478

American (AMR)

AF:

0.0119

AC:

531

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000487

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52612

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000511

AC:

568

AN:

1111766

Other (OTH)

AF:

0.0134

AC:

807

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

364

729

1093

1458

1822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.0511

AC:

7777

AN:

152274

Hom.:

661

Cov.:

AF XY:

0.0491

AC XY:

3658

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.175

AC:

7275

AN:

41516

American (AMR)

AF:

0.0228

AC:

349

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

68018

Other (OTH)

AF:

0.0360

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

305

609

914

1218

1523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0107

Hom.:

Bravo

AF:

0.0586

EpiCase

AF:

0.00104

EpiControl

AF:

0.00131

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.92

(source)

DANN

Benign

0.74

PhyloP100

-1.4

Mutation Taster

=100/0

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