NM_021098.3:c.149C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_021098.3(CACNA1H):c.149C>T(p.Pro50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,438,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P50S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.35

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: Labcorp Genetics (formerly Invitae), G2P
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15974644).

BP6

Variant 16-1153886-C-T is Benign according to our data. Variant chr16-1153886-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 574192.

BS2

High AC in GnomAd4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.149C>T	p.Pro50Leu	missense	Exon 2 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.149C>T	p.Pro50Leu	missense	Exon 2 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.149C>T	p.Pro50Leu	missense	Exon 2 of 35	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6	TSL:1	c.149C>T	p.Pro50Leu	missense	Exon 2 of 34	ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1		c.149C>T	p.Pro50Leu	missense	Exon 2 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes

AF:

0.0000730

AC:

AN:

150646

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000268

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:

0.0000657

AC:

AN:

76064

AF XY:

0.0000456

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000729

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1287634

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

633648

show subpopulations

African (AFR)

AF:

0.000191

AC:

AN:

26150

American (AMR)

AF:

0.00

AC:

AN:

25066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22280

East Asian (EAS)

AF:

0.0000738

AC:

AN:

27106

South Asian (SAS)

AF:

0.0000429

AC:

AN:

69968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3884

European-Non Finnish (NFE)

AF:

0.00000584

AC:

AN:

1027500

Other (OTH)

AF:

0.00

AC:

AN:

52660

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

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:

0.0000730

AC:

AN:

150646

Hom.:

Cov.:

AF XY:

0.0000952

AC XY:

AN XY:

73548

show subpopulations

African (AFR)

AF:

0.000268

AC:

AN:

41078

American (AMR)

AF:

0.00

AC:

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67484

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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:

0.000142

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000170

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV (1)

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.22

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.16

MetaSVM

Uncertain

0.078

MutationAssessor

Benign

0.69

PhyloP100

1.3

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.6

REVEL

Benign

0.18

Sift

Benign

0.30

Sift4G

Benign

0.29

Polyphen

0.020

Vest4

0.076

MutPred

0.22

Loss of glycosylation at P50 (P = 0.0285)

MVP

0.56

ClinPred

0.017

GERP RS

2.0

PromoterAI

0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.082

gMVP

0.33

Mutation Taster

=88/12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over