rs200804807

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_021098.3(CACNA1H):c.1735G>A(p.Asp579Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000366 in 1,552,620 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D579G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.88

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009857684).

BP6

Variant 16-1202185-G-A is Benign according to our data. Variant chr16-1202185-G-A is described in ClinVar as Benign. ClinVar VariationId is 460051.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00174 (265/152332) while in subpopulation AFR AF = 0.00616 (256/41574). AF 95% confidence interval is 0.00554. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 265 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1735G>A	p.Asp579Asn	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.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1696G>A	p.Asp566Asn	missense_variant	Exon 9 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1696G>A	p.Asp566Asn	missense_variant	Exon 9 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.1735G>A	p.Asp579Asn	missense_variant	Exon 9 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000711442.1 link	n.*1182G>A		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.1735G>A		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*1182G>A		3_prime_UTR_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000640028.1 link	n.1385+350G>A		intron_variant	Intron 9 of 34	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

265

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00618

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000395

AC:

AN:

149244

AF XY:

0.000346

show subpopulations

Gnomad AFR exome

AF:

0.00614

Gnomad AMR exome

AF:

0.000201

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000642

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000532

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.000217

AC:

304

AN:

1400288

Hom.:

Cov.:

AF XY:

0.000185

AC XY:

128

AN XY:

691096

show subpopulations

African (AFR)

AF:

0.00664

AC:

210

AN:

31650

American (AMR)

AF:

0.000277

AC:

AN:

36044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25222

East Asian (EAS)

AF:

0.00131

AC:

AN:

35830

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79430

European-Finnish (FIN)

AF:

0.0000211

AC:

AN:

47366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0000167

AC:

AN:

1080942

Other (OTH)

AF:

0.000275

AC:

AN:

58104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

107

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:

0.00174

AC:

265

AN:

152332

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00616

AC:

256

AN:

41574

American (AMR)

AF:

0.000261

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000773

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000341

Hom.:

Bravo

AF:

0.00191

ESP6500AA

AF:

0.00154

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000291

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Benign:1

Jul 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Dec 16, 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

0.16

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

D;D;D;.

MetaRNN

Benign

0.0099

T;T;T;T

MetaSVM

Uncertain

0.097

MutationAssessor

Benign

1.9

L;.;L;L

PhyloP100

3.9

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.6

D;.;D;D

REVEL

Uncertain

0.39

Sift

Benign

0.035

D;.;D;D

Sift4G

Benign

0.12

T;.;T;T

Polyphen

0.027

B;.;P;P

Vest4

0.40

MVP

0.89

ClinPred

0.019

GERP RS

2.8

Varity_R

0.28

gMVP

0.46

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

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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