chr16-1205204-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PP3_ModerateBP6BS1BS2

The NM_021098.3(CACNA1H):c.2542G>A(p.Gly848Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,030 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G848G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.69

Publications

7 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 -7 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

BP6

Variant 16-1205204-G-A is Benign according to our data. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423. Variant chr16-1205204-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 568423.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000184 (28/152314) while in subpopulation AFR AF = 0.000553 (23/41570). AF 95% confidence interval is 0.000378. There are 1 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 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.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.2503G>A	p.Gly835Ser	missense_variant	Exon 11 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.2503G>A	p.Gly835Ser	missense_variant	Exon 11 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2542G>A	p.Gly848Ser	missense_variant	Exon 11 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*455G>A		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*1989G>A		non_coding_transcript_exon_variant	Exon 10 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2542G>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*455G>A		3_prime_UTR_variant	Exon 11 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*1989G>A		3_prime_UTR_variant	Exon 10 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000764

AC:

AN:

248576

AF XY:

0.0000666

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1460716

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726634

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.0000895

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52608

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

1111752

Other (OTH)

AF:

0.0000829

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000184

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41570

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00132

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.000478

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000578

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CACNA1H c.2542G>A (p.Gly848Ser) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 249036 control chromosomes (gnomAD). c.2542G>A has been reported in the literature in a child with epilepsy and Autism Spectrum Disorder (Long_2019). It has also been reported in an individual affected with childhood absence epilepsy who had inherited the variant from their unaffected parent (Chen_2003). This study and another study (PMID: 17696120) following testing of multiple individuals affected with idiopathic generalized epilepsy, including childhood absence epilepsy, concluded that CACNA1H variants represented susceptibility alleles involved in the pathogenesis of a multifactorial disorder. However, no definitive conclusions could be drawn from these studies since no other genes indicated to be associated with the disorder were examined and since there was lack of segregation with disease in the majority of the families assessed. These data do not allow any conclusion about variant significance. Two functional studies were contradictory on their findings and did not allow convincing conclusions about the variant effect. Specifically, one study noted changes in activation and inactivation but not deactivation kinetics for the variant (Peloquin_2006) while the other study showed opposite results finding no alterations in activation and inactivation kinetics but small changes in the deactivation kinetics at very negative voltages (Vitko_2005). A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Benign:1

Oct 28, 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

0.20

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D;.

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;M;M

PhyloP100

9.7

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.8

D;.;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.020

D;.;D;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.88

MVP

0.98

ClinPred

0.79

GERP RS

3.0

Varity_R

0.63

gMVP

0.91

Mutation Taster

=42/58

disease causing

(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