rs57112868

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_021098.3(CACNA1H):c.1381C>T(p.Leu461Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,576,298 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 9 hom., cov: 34)

Exomes 𝑓: 0.00045 ( 7 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.62

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:

LOC124903623 (HGNC:):

LOC124903623 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=-0.36).

BP6

Variant 16-1201831-C-T is Benign according to our data. Variant chr16-1201831-C-T is described in ClinVar as Benign. ClinVar VariationId is 460043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.62 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00472 (719/152366) while in subpopulation AFR AF = 0.0164 (681/41586). AF 95% confidence interval is 0.0154. There are 9 homozygotes in GnomAd4. There are 353 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 719 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 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.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1342C>T	p.Leu448Leu	synonymous_variant	Exon 9 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1342C>T	p.Leu448Leu	synonymous_variant	Exon 9 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.1381C>T	p.Leu461Leu	synonymous_variant	Exon 9 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*828C>T		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.1381C>T		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*828C>T		3_prime_UTR_variant	Exon 8 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00470

AC:

715

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00109

AC:

205

AN:

188826

AF XY:

0.000923

show subpopulations

Gnomad AFR exome

AF:

0.0172

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000496

Gnomad OTH exome

AF:

0.000396

GnomAD4 exome

AF:

0.000449

AC:

640

AN:

1423932

Hom.:

Cov.:

AF XY:

0.000394

AC XY:

278

AN XY:

704902

show subpopulations

African (AFR)

AF:

0.0163

AC:

532

AN:

32630

American (AMR)

AF:

0.000748

AC:

AN:

38782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25442

East Asian (EAS)

AF:

0.00

AC:

AN:

37584

South Asian (SAS)

AF:

0.000111

AC:

AN:

81362

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49512

Middle Eastern (MID)

AF:

0.000710

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.00000914

AC:

AN:

1093880

Other (OTH)

AF:

0.000947

AC:

AN:

59108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00472

AC:

719

AN:

152366

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

353

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0164

AC:

681

AN:

41586

American (AMR)

AF:

0.00170

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

103

138

172

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:

0.00235

Hom.:

Bravo

AF:

0.00557

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 16, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 22, 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

-0.36

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism

(source)

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

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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