16-1201963-C-T

Position:

chr16-1201963-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.1513C>T(p.Arg505Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,544,942 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 7 hom., cov: 34)

Exomes 𝑓: 0.00066 ( 9 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.32

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 links:

CACNA1H (HGNC:):

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065402985).

BP6

Variant 16-1201963-C-T is Benign according to our data. Variant chr16-1201963-C-T is described in ClinVar as [Benign]. Clinvar id is 460049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1201963-C-T is described in Lovd as [Benign]. Variant chr16-1201963-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0063 (960/152312) while in subpopulation AFR AF= 0.022 (913/41566). AF 95% confidence interval is 0.0208. There are 7 homozygotes in gnomad4. There are 462 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 960 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.1513C>T	p.Arg505Cys	missense_variant	9/35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.1513C>T	p.Arg505Cys	missense_variant	9/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.1513C>T	p.Arg505Cys	missense_variant	8/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.1474C>T	p.Arg492Cys	missense_variant	9/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.1513C>T		non_coding_transcript_exon_variant	9/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.1385+128C>T		intron_variant		5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.00631

AC:

960

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00141

AC:

200

AN:

141502

Hom.:

AF XY:

0.00102

AC XY:

AN XY:

76390

show subpopulations

Gnomad AFR exome

AF:

0.0228

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.000856

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000891

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000773

Gnomad OTH exome

AF:

0.000718

GnomAD4 exome

AF:

0.000665

AC:

926

AN:

1392630

Hom.:

Cov.:

AF XY:

0.000541

AC XY:

371

AN XY:

686266

show subpopulations

Gnomad4 AFR exome

AF:

0.0215

Gnomad4 AMR exome

AF:

0.00171

Gnomad4 ASJ exome

AF:

0.00116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.00187

GnomAD4 genome

AF:

0.00630

AC:

960

AN:

152312

Hom.:

Cov.:

AF XY:

0.00620

AC XY:

462

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0220

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.000424

Hom.:

Bravo

AF:

0.00701

ESP6500AA

AF:

0.0135

AC:

ESP6500EA

AF:

0.000141

AC:

ExAC

AF:

0.000893

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 04, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

CACNA1H-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;.;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.82

T;T;T;.

MetaRNN

Benign

0.0065

T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.2

M;.;M;M

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.2

N;.;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.036

D;.;D;D

Sift4G

Uncertain

0.047

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.34

MVP

0.88

ClinPred

0.019

GERP RS

-0.56

Varity_R

0.081

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over