16-1218460-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(CACNA1H):c.5696C>T(p.Pro1899Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000735 in 1,551,544 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. P1899S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 1 hom., cov: 34)

Exomes 𝑓: 0.000075 ( 4 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.186

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036264688).

BP6

Variant 16-1218460-C-T is Benign according to our data. Variant chr16-1218460-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460152.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000591 (9/152296) while in subpopulation SAS AF = 0.00145 (7/4824). AF 95% confidence interval is 0.00068. There are 1 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.5696C>T	p.Pro1899Leu	missense	Exon 33 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.5678C>T	p.Pro1893Leu	missense	Exon 32 of 34	NP_001005407.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.5696C>T	p.Pro1899Leu	missense	Exon 33 of 35	ENSP00000334198.7
CACNA1H	ENST00000569107.6	TSL:1	c.5711C>T	p.Pro1904Leu	missense	Exon 32 of 34	ENSP00000454990.2
CACNA1H	ENST00000711493.1		c.5714C>T	p.Pro1905Leu	missense	Exon 32 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000281

AC:

AN:

156318

AF XY:

0.000265

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00137

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000163

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.0000750

AC:

105

AN:

1399248

Hom.:

Cov.:

AF XY:

0.0000797

AC XY:

AN XY:

690336

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31668

American (AMR)

AF:

0.00120

AC:

AN:

35872

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25178

East Asian (EAS)

AF:

0.00

AC:

AN:

35822

South Asian (SAS)

AF:

0.000567

AC:

AN:

79300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.0000139

AC:

AN:

1079800

Other (OTH)

AF:

0.0000172

AC:

AN:

58110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000591

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41542

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0000718

ExAC

AF:

0.000150

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5696C>T (p.P1899L) alteration is located in exon 33 (coding exon 32) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 5696, causing the proline (P) at amino acid position 1899 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

not provided

Uncertain:1

Apr 17, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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

Benign:1

Aug 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.14

CADD

Benign

5.5

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.036

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.7

PhyloP100

-0.19

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.21

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.054

Polyphen

0.0

Vest4

0.11

MutPred

0.22

Loss of glycosylation at P1900 (P = 0.163)

MVP

0.75

ClinPred

0.050

GERP RS

1.5

Varity_R

0.11

gMVP

0.38

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over