chr16-1195503-C-G

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.483C>G(p.Phe161Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,448,276 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F161F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.04

Publications

7 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, 0.919

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 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.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.444C>G	p.Phe148Leu	missense_variant	Exon 4 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.444C>G	p.Phe148Leu	missense_variant	Exon 4 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.483C>G	p.Phe161Leu	missense_variant	Exon 4 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.483C>G		non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000881

AC:

AN:

227114

AF XY:

0.00

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:

0.0000196

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1448276

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

718856

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33266

American (AMR)

AF:

0.0000234

AC:

AN:

42782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25868

East Asian (EAS)

AF:

0.00

AC:

AN:

39100

South Asian (SAS)

AF:

0.00

AC:

AN:

83462

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.0000217

AC:

AN:

1105714

Other (OTH)

AF:

0.0000167

AC:

AN:

59922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Sep 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Mar 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine with leucine at codon 161 of the CACNA1H protein (p.Phe161Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs119454947, ExAC 0.008%). This missense change has been observed in individual(s) with childhood absence epilepsy (PMID: 12891677). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.93

D;D;D;.

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.4

L;.;L;L

PhyloP100

-1.0

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.0

D;.;D;D

REVEL

Uncertain

0.64

Sift

Benign

0.087

T;.;T;T

Sift4G

Uncertain

0.014

D;.;D;D

Polyphen

0.98

D;.;D;D

Vest4

0.78

MutPred

0.87

Loss of loop (P = 0.1242);.;Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

1.0

ClinPred

0.99

GERP RS

-4.3

Varity_R

0.35

gMVP

0.59

Mutation Taster

=79/21

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over