NM_021098.3:c.2465C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_021098.3(CACNA1H):c.2465C>T(p.Thr822Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,612,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T822S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.92

Publications

1 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_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.896

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.2426C>T	p.Thr809Ile	missense_variant	Exon 11 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.2426C>T	p.Thr809Ile	missense_variant	Exon 11 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2465C>T	p.Thr822Ile	missense_variant	Exon 11 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*378C>T		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*1912C>T		non_coding_transcript_exon_variant	Exon 10 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2465C>T		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*378C>T		3_prime_UTR_variant	Exon 11 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*1912C>T		3_prime_UTR_variant	Exon 10 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000809

AC:

AN:

247334

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.0000653

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1459932

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726278

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51978

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111690

Other (OTH)

AF:

0.0000166

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

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:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000227

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Jul 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 566164). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. This variant is present in population databases (rs369356684, gnomAD 0.008%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 822 of the CACNA1H protein (p.Thr822Ile).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D;.

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.;M;M

PhyloP100

5.9

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.5

D;.;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.016

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Vest4

0.79

ClinPred

0.98

GERP RS

3.9

Varity_R

0.73

gMVP

0.86

Mutation Taster

=43/57

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over