chr16-1211222-A-G

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.4278A>G(p.Ser1426Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,612,144 control chromosomes in the GnomAD database, including 304,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33517 hom., cov: 34)

Exomes 𝑓: 0.61 ( 271398 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.54

Publications

25 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=-0.88).

BP6

Variant 16-1211222-A-G is Benign according to our data. Variant chr16-1211222-A-G is described in ClinVar as Benign. ClinVar VariationId is 585643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.54 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 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.4278A>G	p.Ser1426Ser	synonymous	Exon 22 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.4278A>G	p.Ser1426Ser	synonymous	Exon 22 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.4278A>G	p.Ser1426Ser	synonymous	Exon 22 of 35	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6	TSL:1	c.4278A>G	p.Ser1426Ser	synonymous	Exon 22 of 34	ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1		c.4278A>G	p.Ser1426Ser	synonymous	Exon 22 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes

AF:

0.658

AC:

99933

AN:

151876

Hom.:

33488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.733

Gnomad AMI

AF:

0.571

Gnomad AMR

AF:

0.700

Gnomad ASJ

AF:

0.706

Gnomad EAS

AF:

0.879

Gnomad SAS

AF:

0.570

Gnomad FIN

AF:

0.710

Gnomad MID

AF:

0.712

Gnomad NFE

AF:

0.583

Gnomad OTH

AF:

0.660

GnomAD2 exomes

AF:

0.652

AC:

162023

AN:

248452

AF XY:

0.641

show subpopulations

Gnomad AFR exome

AF:

0.736

Gnomad AMR exome

AF:

0.739

Gnomad ASJ exome

AF:

0.690

Gnomad EAS exome

AF:

0.892

Gnomad FIN exome

AF:

0.696

Gnomad NFE exome

AF:

0.588

Gnomad OTH exome

AF:

0.641

GnomAD4 exome

AF:

0.605

AC:

883958

AN:

1460150

Hom.:

271398

Cov.:

AF XY:

0.603

AC XY:

438145

AN XY:

726402

show subpopulations

African (AFR)

AF:

0.743

AC:

24867

AN:

33472

American (AMR)

AF:

0.732

AC:

32734

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.692

AC:

18082

AN:

26124

East Asian (EAS)

AF:

0.902

AC:

35797

AN:

39692

South Asian (SAS)

AF:

0.571

AC:

49198

AN:

86234

European-Finnish (FIN)

AF:

0.690

AC:

36272

AN:

52574

Middle Eastern (MID)

AF:

0.697

AC:

4014

AN:

5762

European-Non Finnish (NFE)

AF:

0.581

AC:

645110

AN:

1111250

Other (OTH)

AF:

0.628

AC:

37884

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

19601

39202

58803

78404

98005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17958

35916

53874

71832

89790

<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:

0.658

AC:

100007

AN:

151994

Hom.:

33517

Cov.:

AF XY:

0.665

AC XY:

49444

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.732

AC:

30360

AN:

41456

American (AMR)

AF:

0.700

AC:

10704

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.706

AC:

2449

AN:

3470

East Asian (EAS)

AF:

0.878

AC:

4520

AN:

5146

South Asian (SAS)

AF:

0.569

AC:

2749

AN:

4830

European-Finnish (FIN)

AF:

0.710

AC:

7517

AN:

10588

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.583

AC:

39578

AN:

67896

Other (OTH)

AF:

0.665

AC:

1406

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1777

3555

5332

7110

8887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

796

1592

2388

3184

3980

<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:

0.612

Hom.:

77785

Bravo

AF:

0.667

Asia WGS

AF:

0.730

AC:

2537

AN:

3478

EpiCase

AF:

0.599

EpiControl

AF:

0.588

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

-0.88

CADD

Benign

0.073

(source)

DANN

Benign

0.53

PhyloP100

-2.5

Mutation Taster

=74/26

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