chr16-1213837-C-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.4835C>T(p.Ser1612Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000425 in 1,598,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. S1612W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.308

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.135102).

BP6

Variant 16-1213837-C-T is Benign according to our data. Variant chr16-1213837-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529553.

BS2

High AC in GnomAdExome4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4835C>T	p.Ser1612Leu	missense_variant	Exon 27 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.4835C>T	p.Ser1612Leu	missense_variant	Exon 27 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4850C>T	p.Ser1617Leu	missense_variant	Exon 26 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4853C>T	p.Ser1618Leu	missense_variant	Exon 26 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4817C>T	p.Ser1606Leu	missense_variant	Exon 26 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.4850C>T	p.Ser1617Leu	missense_variant	Exon 27 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4835C>T	p.Ser1612Leu	missense_variant	Exon 27 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4796C>T	p.Ser1599Leu	missense_variant	Exon 27 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4817C>T	p.Ser1606Leu	missense_variant	Exon 26 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4778C>T	p.Ser1593Leu	missense_variant	Exon 26 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4835C>T	p.Ser1612Leu	missense_variant	Exon 27 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4817C>T	p.Ser1606Leu	missense_variant	Exon 26 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4835C>T	p.Ser1612Leu	missense_variant	Exon 27 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4835C>T	p.Ser1612Leu	missense_variant	Exon 27 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4835C>T	p.Ser1612Leu	missense_variant	Exon 27 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4835C>T		non_coding_transcript_exon_variant	Exon 27 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*787C>T		non_coding_transcript_exon_variant	Exon 26 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.4773C>T		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*2686C>T		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*4279C>T		non_coding_transcript_exon_variant	Exon 25 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4817C>T		non_coding_transcript_exon_variant	Exon 26 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4817C>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4912C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4835C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4835C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4817C>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4835C>T		non_coding_transcript_exon_variant	Exon 27 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4835C>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4894C>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*787C>T		3_prime_UTR_variant	Exon 26 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1 link	n.*2686C>T		3_prime_UTR_variant	Exon 27 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*4279C>T		3_prime_UTR_variant	Exon 25 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000179

AC:

AN:

223572

AF XY:

0.00000824

show subpopulations

Gnomad AFR exome

AF:

0.000154

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:

0.0000199

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000443

AC:

AN:

1446166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

717898

show subpopulations

African (AFR)

AF:

0.0000901

AC:

AN:

33290

American (AMR)

AF:

0.00

AC:

AN:

42360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25798

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39072

South Asian (SAS)

AF:

0.00

AC:

AN:

83726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000534

AC:

AN:

1105576

Other (OTH)

AF:

0.0000167

AC:

AN:

59846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

152272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000195

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2114

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

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:

0.0000216

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000240

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Uncertain:1

Aug 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CACNA1H c.4835C>T variant is predicted to result in the amino acid substitution p.Ser1612Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Hyperaldosteronism, familial, type IV

Uncertain:1

Mar 05, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;.;.;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.59

LIST_S2

Pathogenic

0.97

D;D;D;.

M_CAP

Benign

0.081

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Uncertain

0.098

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

0.31

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.5

D;.;D;D

Sift

Benign

0.12

T;.;T;T

Sift4G

Benign

0.17

T;.;T;T

Vest4

0.57

ClinPred

0.36

GERP RS

2.8

Varity_R

0.37

gMVP

0.63

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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