NM_021098.3:c.733G>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_021098.3(CACNA1H):c.733G>T(p.Gly245Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G245S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.43

Publications

0 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.694G>T	p.Gly232Cys	missense_variant	Exon 6 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.694G>T	p.Gly232Cys	missense_variant	Exon 6 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.733G>T	p.Gly245Cys	missense_variant	Exon 6 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*180G>T		non_coding_transcript_exon_variant	Exon 5 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.733G>T		non_coding_transcript_exon_variant	Exon 6 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*180G>T		3_prime_UTR_variant	Exon 5 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461160

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111660

Other (OTH)

AF:

0.0000166

AC:

AN:

60344

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

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;.

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;.;M;M

PhyloP100

7.4

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.9

D;.;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.012

D;.;D;D

Vest4

0.84

ClinPred

1.0

GERP RS

3.6

Varity_R

0.97

gMVP

0.98

Mutation Taster

=25/75

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over