rs58110336

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The ENST00000711450.1(CACNA1H):c.4573C>T(p.Arg1525Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,552 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0082 ( 14 hom., cov: 33)

Exomes 𝑓: 0.00082 ( 19 hom. )

Consequence

CACNA1H
ENST00000711450.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.314

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 16-1212014-C-T is Benign according to our data. Variant chr16-1212014-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00823 (1254/152344) while in subpopulation AFR AF = 0.0286 (1188/41566). AF 95% confidence interval is 0.0272. There are 14 homozygotes in GnomAd4. There are 568 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1254 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000711450.1 link	c.4573C>T	p.Arg1525Cys	missense_variant	Exon 25 of 35			ENSP00000518762.1
CACNA1H	ENST00000348261.11 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4671C>T	p.Phe1557Phe	synonymous_variant	Exon 25 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000564231.6 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4596C>T	p.Phe1532Phe	synonymous_variant	Exon 25 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4596C>T	p.Phe1532Phe	synonymous_variant	Exon 25 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4635C>T	p.Phe1545Phe	synonymous_variant	Exon 25 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*605C>T		non_coding_transcript_exon_variant	Exon 25 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4573C>T		non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2486C>T		non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4020C>T		non_coding_transcript_exon_variant	Exon 24 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4635C>T		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*605C>T		3_prime_UTR_variant	Exon 25 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2486C>T		3_prime_UTR_variant	Exon 25 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4020C>T		3_prime_UTR_variant	Exon 24 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00822

AC:

1252

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0286

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

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:

0.0000882

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00225

AC:

560

AN:

249104

AF XY:

0.00158

show subpopulations

Gnomad AFR exome

AF:

0.0313

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000797

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000820

AC:

1198

AN:

1461208

Hom.:

Cov.:

AF XY:

0.000718

AC XY:

522

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.0285

AC:

953

AN:

33462

American (AMR)

AF:

0.00186

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.000353

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.0000360

AC:

AN:

1111678

Other (OTH)

AF:

0.00192

AC:

116

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

150

225

300

375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00823

AC:

1254

AN:

152344

Hom.:

Cov.:

AF XY:

0.00762

AC XY:

568

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0286

AC:

1188

AN:

41566

American (AMR)

AF:

0.00281

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68030

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00399

Hom.:

Bravo

AF:

0.00919

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 22, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 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

AlphaMissense

Benign

0.29

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

-0.31

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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