16-1208114-C-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.3256C>T(p.Pro1086Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,168 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 (★).

Frequency

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

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.45

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=0.30896127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.3217C>T	p.Pro1073Ser	missense_variant	Exon 16 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.3217C>T	p.Pro1073Ser	missense_variant	Exon 16 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3256C>T	p.Pro1086Ser	missense_variant	Exon 16 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*1169C>T		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2703C>T		non_coding_transcript_exon_variant	Exon 15 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3256C>T		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1169C>T		3_prime_UTR_variant	Exon 16 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*2703C>T		3_prime_UTR_variant	Exon 15 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715688

African (AFR)

AF:

0.00

AC:

AN:

32916

American (AMR)

AF:

0.00

AC:

AN:

42566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25774

East Asian (EAS)

AF:

0.00

AC:

AN:

38432

South Asian (SAS)

AF:

0.00

AC:

AN:

82766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5364

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103858

Other (OTH)

AF:

0.00

AC:

AN:

59678

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

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

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:

0.00

Hom.:

Bravo

AF:

0.0000151

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

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function. 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. ClinVar contains an entry for this variant (Variation ID: 529576). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1086 of the CACNA1H protein (p.Pro1086Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.0073

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.47

T;.;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;T;T;.

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.2

M;.;M;M

PhyloP100

4.4

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.4

D;.;D;D

REVEL

Benign

0.23

Sift

Benign

0.61

T;.;T;T

Sift4G

Benign

0.32

T;.;T;T

Polyphen

1.0

D;.;P;P

Vest4

0.46

MutPred

0.16

Gain of phosphorylation at P1086 (P = 0.0302);.;Gain of phosphorylation at P1086 (P = 0.0302);Gain of phosphorylation at P1086 (P = 0.0302);

MVP

0.92

ClinPred

0.98

GERP RS

4.0

Varity_R

0.22

gMVP

0.37

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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