16-1210818-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021098.3(CACNA1H):c.4070A>T(p.His1357Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,602,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H1357H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4031A>T	p.His1344Leu	missense_variant	Exon 21 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4031A>T	p.His1344Leu	missense_variant	Exon 21 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4070A>T	p.His1357Leu	missense_variant	Exon 21 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*40A>T		non_coding_transcript_exon_variant	Exon 21 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*1983A>T		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3517A>T		non_coding_transcript_exon_variant	Exon 20 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4070A>T		non_coding_transcript_exon_variant	Exon 21 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*40A>T		3_prime_UTR_variant	Exon 21 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1 link	n.*1983A>T		3_prime_UTR_variant	Exon 21 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3517A>T		3_prime_UTR_variant	Exon 20 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152242

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

240472

AF XY:

0.00000759

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:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1450702

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111680

Other (OTH)

AF:

0.0000332

AC:

AN:

60272

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:

0.0000263

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000284

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000826

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine with leucine at codon 1357 of the CACNA1H protein (p.His1357Leu). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is present in population databases (rs775971172, ExAC 0.002%). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNA1H-related disease. ClinVar contains an entry for this variant (Variation ID:¬¨‚Ä†529589).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.77

D;.;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.92

D;D;D;.

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.50

D;D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.58

N;.;N;N

PhyloP100

2.9

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.0

D;.;D;D

REVEL

Uncertain

0.42

Sift

Benign

0.032

D;.;D;D

Sift4G

Uncertain

0.039

D;.;D;D

Vest4

0.51

ClinPred

0.78

GERP RS

2.0

Varity_R

0.11

gMVP

0.53

Mutation Taster

=76/24

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over