rs58764017

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_021098.3(CACNA1H):c.4932G>A(p.Ser1644Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,603,918 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 8 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.15

Publications

1 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=-0.72).

BP6

Variant 16-1214974-G-A is Benign according to our data. Variant chr16-1214974-G-A is described in ClinVar as Benign. ClinVar VariationId is 529688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00526 (802/152332) while in subpopulation AFR AF = 0.0178 (741/41568). AF 95% confidence interval is 0.0168. There are 4 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 802 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4932G>A	p.Ser1644Ser	splice_region_variant, synonymous_variant	Exon 28 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.4932G>A	p.Ser1644Ser	splice_region_variant, synonymous_variant	Exon 28 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4947G>A	p.Ser1649Ser	splice_region_variant, synonymous_variant	Exon 27 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4950G>A	p.Ser1650Ser	splice_region_variant, synonymous_variant	Exon 27 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4914G>A	p.Ser1638Ser	splice_region_variant, synonymous_variant	Exon 27 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.4947G>A	p.Ser1649Ser	splice_region_variant, synonymous_variant	Exon 28 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4932G>A	p.Ser1644Ser	splice_region_variant, synonymous_variant	Exon 28 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4893G>A	p.Ser1631Ser	splice_region_variant, synonymous_variant	Exon 28 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4914G>A	p.Ser1638Ser	splice_region_variant, synonymous_variant	Exon 27 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4875G>A	p.Ser1625Ser	splice_region_variant, synonymous_variant	Exon 27 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4932G>A	p.Ser1644Ser	splice_region_variant, synonymous_variant	Exon 28 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4914G>A	p.Ser1638Ser	splice_region_variant, synonymous_variant	Exon 27 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4932G>A	p.Ser1644Ser	splice_region_variant, synonymous_variant	Exon 28 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4932G>A	p.Ser1644Ser	splice_region_variant, synonymous_variant	Exon 28 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4932G>A	p.Ser1644Ser	splice_region_variant, synonymous_variant	Exon 28 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4932G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*884G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 27 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*13G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*2783G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*4376G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 26 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4914G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4914G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 27 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.5009G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4932G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4932G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4914G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 27 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4932G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4932G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4991G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 27 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*884G>A		3_prime_UTR_variant	Exon 27 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*13G>A		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*2783G>A		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*4376G>A		3_prime_UTR_variant	Exon 26 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00527

AC:

802

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00115

AC:

268

AN:

233822

AF XY:

0.000828

show subpopulations

Gnomad AFR exome

AF:

0.0173

Gnomad AMR exome

AF:

0.000757

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000474

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000560

AC:

813

AN:

1451586

Hom.:

Cov.:

AF XY:

0.000466

AC XY:

336

AN XY:

721038

show subpopulations

African (AFR)

AF:

0.0189

AC:

629

AN:

33274

American (AMR)

AF:

0.00104

AC:

AN:

43444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

39368

South Asian (SAS)

AF:

0.000166

AC:

AN:

84456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52330

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000434

AC:

AN:

1107062

Other (OTH)

AF:

0.00117

AC:

AN:

60038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00526

AC:

802

AN:

152332

Hom.:

Cov.:

AF XY:

0.00497

AC XY:

370

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0178

AC:

741

AN:

41568

American (AMR)

AF:

0.00248

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68024

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

121

162

202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00158

Hom.:

Bravo

AF:

0.00627

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Aug 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.051

(source)

DANN

Benign

0.89

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(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