16-1219096-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021098.3(CACNA1H):c.6014G>T(p.Arg2005Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,540 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2005C) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0550

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24184072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6014G>T	p.Arg2005Leu	missense_variant	Exon 34 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.6014G>T	p.Arg2005Leu	missense_variant	Exon 34 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.6029G>T	p.Arg2010Leu	missense_variant	Exon 33 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.5999G>T	p.Arg2000Leu	missense_variant	Exon 33 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5996G>T	p.Arg1999Leu	missense_variant	Exon 33 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.5996G>T	p.Arg1999Leu	missense_variant	Exon 34 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5981G>T	p.Arg1994Leu	missense_variant	Exon 34 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.5975G>T	p.Arg1992Leu	missense_variant	Exon 34 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.5963G>T	p.Arg1988Leu	missense_variant	Exon 33 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.5957G>T	p.Arg1986Leu	missense_variant	Exon 33 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.6014G>T	p.Arg2005Leu	missense_variant	Exon 34 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5963G>T	p.Arg1988Leu	missense_variant	Exon 33 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5936G>T	p.Arg1979Leu	missense_variant	Exon 34 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.6014G>T	p.Arg2005Leu	missense_variant	Exon 34 of 35			ENSP00000518772.1
CACNA1H	ENST00000621827.2 link	n.6014G>T		non_coding_transcript_exon_variant	Exon 34 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1933G>T		non_coding_transcript_exon_variant	Exon 33 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1062G>T		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*3832G>T		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5458G>T		non_coding_transcript_exon_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*955G>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*873G>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1593G>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*681G>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*648G>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5963G>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6014G>T		non_coding_transcript_exon_variant	Exon 34 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5981G>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1130G>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1933G>T		3_prime_UTR_variant	Exon 33 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1062G>T		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*3832G>T		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5458G>T		3_prime_UTR_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*955G>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*873G>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1593G>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*681G>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*648G>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1 link	n.*1130G>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000711456.1 link	c.5887+445G>T		intron_variant	Intron 33 of 33			ENSP00000518769.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1394540

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31554

American (AMR)

AF:

0.00

AC:

AN:

35546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25060

East Asian (EAS)

AF:

0.00

AC:

AN:

35648

South Asian (SAS)

AF:

0.00

AC:

AN:

79048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077092

Other (OTH)

AF:

0.00

AC:

AN:

57812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

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

Mar 30, 2020

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1H-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces arginine with leucine at codon 2005 of the CACNA1H protein (p.Arg2005Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

6.8

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.51

D;.;.;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.69

T;T;T;.

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.2

M;.;.;.

PhyloP100

0.055

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.2

D;.;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.0070

D;.;D;D

Sift4G

Benign

0.24

T;.;T;T

Vest4

0.36

ClinPred

0.83

GERP RS

1.0

Varity_R

0.17

gMVP

0.34

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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