rs72552053

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_021098.3(CACNA1H):c.5825C>T(p.Ala1942Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 1,565,426 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1942S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000038 ( 2 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.590

Publications

0 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10128817).

BP6

Variant 16-1218589-C-T is Benign according to our data. Variant chr16-1218589-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529550.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000145 (22/152188) while in subpopulation AFR AF = 0.000482 (20/41518). AF 95% confidence interval is 0.000319. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5825C>T	p.Ala1942Val	missense_variant	Exon 33 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.5825C>T	p.Ala1942Val	missense_variant	Exon 33 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5840C>T	p.Ala1947Val	missense_variant	Exon 32 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5843C>T	p.Ala1948Val	missense_variant	Exon 32 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5807C>T	p.Ala1936Val	missense_variant	Exon 32 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5840C>T	p.Ala1947Val	missense_variant	Exon 33 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5825C>T	p.Ala1942Val	missense_variant	Exon 33 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5786C>T	p.Ala1929Val	missense_variant	Exon 33 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5807C>T	p.Ala1936Val	missense_variant	Exon 32 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5768C>T	p.Ala1923Val	missense_variant	Exon 32 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5825C>T	p.Ala1942Val	missense_variant	Exon 33 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5807C>T	p.Ala1936Val	missense_variant	Exon 32 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5825C>T	p.Ala1942Val	missense_variant	Exon 33 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5825C>T	p.Ala1942Val	missense_variant	Exon 33 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5825C>T	p.Ala1942Val	missense_variant	Exon 33 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5825C>T		non_coding_transcript_exon_variant	Exon 33 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1777C>T		non_coding_transcript_exon_variant	Exon 32 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*906C>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3676C>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5269C>T		non_coding_transcript_exon_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*799C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*684C>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1437C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*492C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*492C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5807C>T		non_coding_transcript_exon_variant	Exon 32 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5825C>T		non_coding_transcript_exon_variant	Exon 33 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5825C>T		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*941C>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1777C>T		3_prime_UTR_variant	Exon 32 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*906C>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3676C>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5269C>T		3_prime_UTR_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*799C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*684C>T		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1437C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*492C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*492C>T		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1 link	n.*941C>T		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000686

AC:

AN:

174838

AF XY:

0.0000745

show subpopulations

Gnomad AFR exome

AF:

0.000207

Gnomad AMR exome

AF:

0.000113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000156

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000139

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000382

AC:

AN:

1413238

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

698444

show subpopulations

African (AFR)

AF:

0.000462

AC:

AN:

32446

American (AMR)

AF:

0.000106

AC:

AN:

37686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25324

East Asian (EAS)

AF:

0.0000538

AC:

AN:

37184

South Asian (SAS)

AF:

0.000174

AC:

AN:

80364

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

1087240

Other (OTH)

AF:

0.0000854

AC:

AN:

58564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000145

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

41518

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000107

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000250

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000427

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5825C>T (p.A1942V) alteration is located in exon 33 (coding exon 32) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 5825, causing the alanine (A) at amino acid position 1942 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.14

CADD

Benign

3.3

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.19

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.63

T;T;T;.

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Uncertain

0.011

MutationAssessor

Benign

1.8

L;.;.;.

PhyloP100

0.59

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

N;.;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.13

T;.;T;T

Sift4G

Benign

0.32

T;.;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.13

MVP

0.84

ClinPred

0.011

GERP RS

-0.20

Varity_R

0.048

gMVP

0.40

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