rs200709671

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_021098.3(CACNA1H):c.4534G>A(p.Asp1512Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,612,598 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D1512D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.38

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.402332).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 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.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4570G>A	p.Asp1524Asn	missense_variant	Exon 24 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4495G>A	p.Asp1499Asn	missense_variant	Exon 24 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4495G>A	p.Asp1499Asn	missense_variant	Exon 24 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4534G>A	p.Asp1512Asn	missense_variant	Exon 24 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*504G>A		non_coding_transcript_exon_variant	Exon 24 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2447G>A		non_coding_transcript_exon_variant	Exon 24 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3981G>A		non_coding_transcript_exon_variant	Exon 23 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4534G>A		non_coding_transcript_exon_variant	Exon 24 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*504G>A		3_prime_UTR_variant	Exon 24 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2447G>A		3_prime_UTR_variant	Exon 24 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3981G>A		3_prime_UTR_variant	Exon 23 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000113

AC:

AN:

248402

AF XY:

0.000141

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000897

AC:

131

AN:

1460376

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

726482

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.0000894

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000209

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000382

AC:

AN:

52302

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000891

AC:

AN:

1111708

Other (OTH)

AF:

0.0000994

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.0000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000413

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000335

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000578

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4534G>A (p.D1512N) alteration is located in exon 24 (coding exon 23) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 4534, causing the aspartic acid (D) at amino acid position 1512 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1512 of the CACNA1H protein (p.Asp1512Asn). This variant is present in population databases (rs200709671, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 460117). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;.;.;.

Eigen

Benign

-0.024

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

D;D;T;.

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.40

T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.55

N;.;N;N

PhyloP100

3.4

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.1

D;.;D;D

REVEL

Uncertain

0.46

Sift

Benign

0.29

T;.;T;T

Sift4G

Benign

0.50

T;.;T;T

Polyphen

0.45

B;.;B;B

Vest4

0.41

MVP

0.95

ClinPred

0.20

GERP RS

4.5

Varity_R

0.51

gMVP

0.83

Mutation Taster

=65/35

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