rs58597457

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(CACNA1H):c.6848A>G(p.Asp2283Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,612,370 control chromosomes in the GnomAD database, including 1 homozygotes. 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. D2283V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.66

Publications

4 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028550178).

BP6

Variant 16-1220780-A-G is Benign according to our data. Variant chr16-1220780-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1094390.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000698 (102/1460482) while in subpopulation SAS AF = 0.00107 (92/86258). AF 95% confidence interval is 0.00089. There are 1 homozygotes in GnomAdExome4. There are 79 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6848A>G	p.Asp2283Gly	missense_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.6848A>G	p.Asp2283Gly	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.6863A>G	p.Asp2288Gly	missense_variant	Exon 34 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.6833A>G	p.Asp2278Gly	missense_variant	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.6830A>G	p.Asp2277Gly	missense_variant	Exon 34 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.6830A>G	p.Asp2277Gly	missense_variant	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.6815A>G	p.Asp2272Gly	missense_variant	Exon 35 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.6809A>G	p.Asp2270Gly	missense_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.6797A>G	p.Asp2266Gly	missense_variant	Exon 34 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.6791A>G	p.Asp2264Gly	missense_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000637236.3 link	n.*2767A>G		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1896A>G		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*4666A>G		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*6292A>G		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1789A>G		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1707A>G		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*2427A>G		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*1515A>G		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*1482A>G		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*762A>G		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6848A>G		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.6815A>G		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1964A>G		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711482.1 link	c.*327A>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.*327A>G		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.*327A>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.*762A>G		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.*762A>G		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3 link	n.*2767A>G		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1896A>G		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*4666A>G		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*6292A>G		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1789A>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1707A>G		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*2427A>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*1515A>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*1482A>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*762A>G		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1 link	n.*1964A>G		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000621827.2 link	n.6121+727A>G		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151768

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:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000141

AC:

AN:

248380

AF XY:

0.000185

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1460482

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00107

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52246

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111822

Other (OTH)

AF:

0.000149

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.0000198

AC:

AN:

151888

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.000623

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67878

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000190

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Benign

0.018

Eigen_PC

Benign

-0.030

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.77

T;T;T;.

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.029

T;T;T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

0.97

L;.;.;.

PhyloP100

1.7

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

N;.;N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.025

D;.;D;D

Sift4G

Benign

0.10

T;.;T;T

Polyphen

0.99

D;.;B;B

Vest4

0.29

MutPred

0.10

Gain of relative solvent accessibility (P = 0.0249);.;.;.;

MVP

0.87

ClinPred

0.27

GERP RS

4.0

Varity_R

0.22

gMVP

0.19

Mutation Taster

=86/14

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over