NM_021098.3:c.4275A>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.4275A>G(p.Ser1425Ser) 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 1,612,062 control chromosomes in the GnomAD database, including 304,869 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. S1425S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.66 ( 33496 hom., cov: 35)

Exomes 𝑓: 0.61 ( 271373 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.37

Publications

23 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=-0.81).

BP6

Variant 16-1211219-A-G is Benign according to our data. Variant chr16-1211219-A-G is described in ClinVar as Benign. ClinVar VariationId is 585642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4275A>G	p.Ser1425Ser	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.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4236A>G	p.Ser1412Ser	synonymous_variant	Exon 22 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4236A>G	p.Ser1412Ser	synonymous_variant	Exon 22 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4275A>G	p.Ser1425Ser	synonymous_variant	Exon 22 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*245A>G		non_coding_transcript_exon_variant	Exon 22 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2188A>G		non_coding_transcript_exon_variant	Exon 22 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3722A>G		non_coding_transcript_exon_variant	Exon 21 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4275A>G		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*245A>G		3_prime_UTR_variant	Exon 22 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2188A>G		3_prime_UTR_variant	Exon 22 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3722A>G		3_prime_UTR_variant	Exon 21 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.658

AC:

99901

AN:

151880

Hom.:

33467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.732

Gnomad AMI

AF:

0.571

Gnomad AMR

AF:

0.700

Gnomad ASJ

AF:

0.706

Gnomad EAS

AF:

0.879

Gnomad SAS

AF:

0.569

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:

161970

AN:

248412

AF XY:

0.641

show subpopulations

Gnomad AFR exome

AF:

0.735

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:

883872

AN:

1460064

Hom.:

271373

Cov.:

AF XY:

0.603

AC XY:

438091

AN XY:

726346

show subpopulations

African (AFR)

AF:

0.743

AC:

24852

AN:

33466

American (AMR)

AF:

0.732

AC:

32729

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.692

AC:

18078

AN:

26120

East Asian (EAS)

AF:

0.902

AC:

35791

AN:

39690

South Asian (SAS)

AF:

0.571

AC:

49203

AN:

86222

European-Finnish (FIN)

AF:

0.690

AC:

36251

AN:

52546

Middle Eastern (MID)

AF:

0.697

AC:

4017

AN:

5766

European-Non Finnish (NFE)

AF:

0.581

AC:

645073

AN:

1111218

Other (OTH)

AF:

0.628

AC:

37878

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

19637

39274

58910

78547

98184

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:

99975

AN:

151998

Hom.:

33496

Cov.:

AF XY:

0.665

AC XY:

49429

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.732

AC:

30337

AN:

41454

American (AMR)

AF:

0.700

AC:

10703

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.706

AC:

2449

AN:

3470

East Asian (EAS)

AF:

0.878

AC:

4518

AN:

5144

South Asian (SAS)

AF:

0.569

AC:

2746

AN:

4826

European-Finnish (FIN)

AF:

0.710

AC:

7515

AN:

10588

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.583

AC:

39577

AN:

67912

Other (OTH)

AF:

0.665

AC:

1406

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1788

3576

5363

7151

8939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<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:

0.614

Hom.:

12584

Bravo

AF:

0.667

Asia WGS

AF:

0.730

AC:

2539

AN:

3478

EpiCase

AF:

0.599

EpiControl

AF:

0.587

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.81

CADD

Benign

0.052

(source)

DANN

Benign

0.46

PhyloP100

-3.4

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