NM_021098.3:c.5C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_021098.3(CACNA1H):c.5C>T(p.Thr2Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. T2N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 9.4e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.112

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40384805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 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.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5C>T	p.Thr2Ile	missense_variant	Exon 2 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

150962

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.44e-7

AC:

AN:

1058838

Hom.:

Cov.:

AF XY:

0.00000200

AC XY:

AN XY:

500732

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21622

American (AMR)

AF:

0.00

AC:

AN:

7304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12804

East Asian (EAS)

AF:

0.00

AC:

AN:

23358

South Asian (SAS)

AF:

0.00

AC:

AN:

22136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2756

European-Non Finnish (NFE)

AF:

0.00000110

AC:

AN:

906410

Other (OTH)

AF:

0.00

AC:

AN:

41536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000662

AC:

AN:

150962

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73720

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41262

American (AMR)

AF:

0.00

AC:

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5072

South Asian (SAS)

AF:

0.000208

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67626

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.43

T;T;T;.

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.40

T;T;T;T

MetaSVM

Uncertain

-0.097

MutationAssessor

Benign

1.1

L;.;L;L

PhyloP100

0.11

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.85

N;.;N;N

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Benign

0.076

T;.;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.11

MutPred

0.25

Loss of phosphorylation at T2 (P = 0.0325);Loss of phosphorylation at T2 (P = 0.0325);Loss of phosphorylation at T2 (P = 0.0325);Loss of phosphorylation at T2 (P = 0.0325);

MVP

0.49

ClinPred

0.33

GERP RS

0.71

PromoterAI

0.062

Neutral

(source)

Varity_R

0.14

gMVP

0.39

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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NM_021098.3:c.5C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over