rs745354512

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_021098.3(CACNA1H):c.3082G>A(p.Asp1028Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00004 in 1,600,472 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1028E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.38

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31936654).

BP6

Variant 16-1207788-G-A is Benign according to our data. Variant chr16-1207788-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460076.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 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.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3043G>A	p.Asp1015Asn	missense_variant	Exon 15 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3043G>A	p.Asp1015Asn	missense_variant	Exon 15 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3082G>A	p.Asp1028Asn	missense_variant	Exon 15 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*995G>A		non_coding_transcript_exon_variant	Exon 15 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2529G>A		non_coding_transcript_exon_variant	Exon 14 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3082G>A		non_coding_transcript_exon_variant	Exon 15 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*995G>A		3_prime_UTR_variant	Exon 15 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2529G>A		3_prime_UTR_variant	Exon 14 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000309

AC:

AN:

226632

AF XY:

0.0000407

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000123

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000492

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000400

AC:

AN:

1448276

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

719218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33192

American (AMR)

AF:

0.00

AC:

AN:

42980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25908

East Asian (EAS)

AF:

0.000180

AC:

AN:

38800

South Asian (SAS)

AF:

0.0000239

AC:

AN:

83760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000434

AC:

AN:

1105966

Other (OTH)

AF:

0.0000167

AC:

AN:

59880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

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:

0.0000508

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Jan 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3082G>A (p.D1028N) alteration is located in exon 15 (coding exon 14) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 3082, causing the aspartic acid (D) at amino acid position 1028 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

Benign:1

Aug 29, 2024

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

0.10

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;.;.

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.064

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;D;D;.

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.32

T;T;T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.4

M;.;M;M

PhyloP100

4.4

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.5

N;.;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.030

D;.;D;D

Sift4G

Benign

0.33

T;.;T;T

Polyphen

1.0

D;.;D;D

Vest4

0.56

MutPred

0.25

Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.93

ClinPred

0.38

GERP RS

3.6

Varity_R

0.15

gMVP

0.39

Mutation Taster

=69/31

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