rs79829712

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021098.3(CACNA1H):c.888C>A(p.Asp296Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,634 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D296D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0970

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22837731).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 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.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.849C>A	p.Asp283Glu	missense_variant	Exon 7 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.849C>A	p.Asp283Glu	missense_variant	Exon 7 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.888C>A	p.Asp296Glu	missense_variant	Exon 7 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*335C>A		non_coding_transcript_exon_variant	Exon 6 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.888C>A		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*335C>A		3_prime_UTR_variant	Exon 6 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152246

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1450388

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

720562

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33242

American (AMR)

AF:

0.00

AC:

AN:

43554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25800

East Asian (EAS)

AF:

0.00

AC:

AN:

39210

South Asian (SAS)

AF:

0.00

AC:

AN:

84892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1107296

Other (OTH)

AF:

0.00

AC:

AN:

59948

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 18, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Uncertain

0.49

T;.;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.84

T;T;T;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Uncertain

-0.019

MutationAssessor

Benign

0.29

N;.;N;N

PhyloP100

0.097

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.070

N;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.93

T;.;T;T

Sift4G

Benign

0.56

T;.;T;T

Polyphen

0.020

B;.;B;B

Vest4

0.33

MutPred

0.39

Gain of sheet (P = 0.0085);.;Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);

MVP

0.64

ClinPred

0.45

GERP RS

3.5

Varity_R

0.045

gMVP

0.84

Mutation Taster

=73/27

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over