rs532223684

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.1517G>A(p.Arg506Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,544,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R506G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.89

Publications

2 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=0.022917151).

BP6

Variant 16-1201967-G-A is Benign according to our data. Variant chr16-1201967-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529607.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000243 (37/152260) while in subpopulation AMR AF = 0.00131 (20/15310). AF 95% confidence interval is 0.000865. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 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.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1478G>A	p.Arg493Gln	missense_variant	Exon 9 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1478G>A	p.Arg493Gln	missense_variant	Exon 9 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.1517G>A	p.Arg506Gln	missense_variant	Exon 9 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000711442.1 link	n.*964G>A		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.1517G>A		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*964G>A		3_prime_UTR_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000640028.1 link	n.1385+132G>A		intron_variant	Intron 9 of 34	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000206

AC:

AN:

140622

AF XY:

0.000211

show subpopulations

Gnomad AFR exome

AF:

0.000153

Gnomad AMR exome

AF:

0.000246

Gnomad ASJ exome

AF:

0.000734

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.000480

GnomAD4 exome

AF:

0.000141

AC:

196

AN:

1391996

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

685902

show subpopulations

African (AFR)

AF:

0.0000635

AC:

AN:

31490

American (AMR)

AF:

0.000422

AC:

AN:

35582

Ashkenazi Jewish (ASJ)

AF:

0.000717

AC:

AN:

25088

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35616

South Asian (SAS)

AF:

0.000202

AC:

AN:

79112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5584

European-Non Finnish (NFE)

AF:

0.000115

AC:

124

AN:

1076306

Other (OTH)

AF:

0.000346

AC:

AN:

57798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000243

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41548

American (AMR)

AF:

0.00131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67994

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.000264

ExAC

AF:

0.000110

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Dec 21, 2017

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Uncertain:1

May 16, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PM2 -

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

Benign:1

Jan 15, 2025

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

0.086

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.15

T;.;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.73

T;T;T;.

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.023

T;T;T;T

MetaSVM

Uncertain

0.019

MutationAssessor

Benign

1.7

L;.;L;L

PhyloP100

1.9

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

N;.;N;N

REVEL

Benign

0.23

Sift

Benign

0.59

T;.;T;T

Sift4G

Benign

0.22

T;.;T;T

Polyphen

0.0070

B;.;B;B

Vest4

0.096

MutPred

0.38

Loss of MoRF binding (P = 0.0846);.;Loss of MoRF binding (P = 0.0846);Loss of MoRF binding (P = 0.0846);

MVP

0.76

ClinPred

0.012

GERP RS

2.9

Varity_R

0.085

gMVP

0.32

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs532223684

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