rs58033848

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.4836G>A(p.Ser1612Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,598,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1612S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.97

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: 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 16-1213838-G-A is Benign according to our data. Variant chr16-1213838-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000592 (9/152082) while in subpopulation AMR AF = 0.000589 (9/15290). AF 95% confidence interval is 0.000307. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4836G>A	p.Ser1612Ser	synonymous_variant	Exon 27 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.4836G>A	p.Ser1612Ser	synonymous_variant	Exon 27 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4851G>A	p.Ser1617Ser	synonymous_variant	Exon 26 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4854G>A	p.Ser1618Ser	synonymous_variant	Exon 26 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4818G>A	p.Ser1606Ser	synonymous_variant	Exon 26 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.4851G>A	p.Ser1617Ser	synonymous_variant	Exon 27 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4836G>A	p.Ser1612Ser	synonymous_variant	Exon 27 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4797G>A	p.Ser1599Ser	synonymous_variant	Exon 27 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4818G>A	p.Ser1606Ser	synonymous_variant	Exon 26 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4779G>A	p.Ser1593Ser	synonymous_variant	Exon 26 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4836G>A	p.Ser1612Ser	synonymous_variant	Exon 27 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4818G>A	p.Ser1606Ser	synonymous_variant	Exon 26 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4836G>A	p.Ser1612Ser	synonymous_variant	Exon 27 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4836G>A	p.Ser1612Ser	synonymous_variant	Exon 27 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4836G>A	p.Ser1612Ser	synonymous_variant	Exon 27 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4836G>A		non_coding_transcript_exon_variant	Exon 27 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*788G>A		non_coding_transcript_exon_variant	Exon 26 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.4774G>A		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*2687G>A		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*4280G>A		non_coding_transcript_exon_variant	Exon 25 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4818G>A		non_coding_transcript_exon_variant	Exon 26 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4818G>A		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4913G>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4836G>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4836G>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4818G>A		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4836G>A		non_coding_transcript_exon_variant	Exon 27 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4836G>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4895G>A		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*788G>A		3_prime_UTR_variant	Exon 26 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1 link	n.*2687G>A		3_prime_UTR_variant	Exon 27 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*4280G>A		3_prime_UTR_variant	Exon 25 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000431

AC:

AN:

224990

AF XY:

0.000377

show subpopulations

Gnomad AFR exome

AF:

0.0000762

Gnomad AMR exome

AF:

0.00277

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000197

Gnomad OTH exome

AF:

0.000357

GnomAD4 exome

AF:

0.0000836

AC:

121

AN:

1446890

Hom.:

Cov.:

AF XY:

0.0000835

AC XY:

AN XY:

718278

show subpopulations

African (AFR)

AF:

0.0000901

AC:

AN:

33306

American (AMR)

AF:

0.00247

AC:

105

AN:

42488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25820

East Asian (EAS)

AF:

0.000128

AC:

AN:

39110

South Asian (SAS)

AF:

0.0000716

AC:

AN:

83836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50780

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1105928

Other (OTH)

AF:

0.00

AC:

AN:

59882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000592

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.000589

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000230

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Benign:1

Jun 25, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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

Benign:1

Oct 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Nov 03, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.56

(source)

DANN

Benign

0.84

PhyloP100

-4.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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