16-1202369-C-T

Position:

chr16-1202369-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021098.3(CACNA1H):c.1919C>T(p.Pro640Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,557,154 control chromosomes in the GnomAD database, including 78,216 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8504 hom., cov: 34)

Exomes 𝑓: 0.29 ( 69712 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.07

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:

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=1.2459473E-6).

BP6

Variant 16-1202369-C-T is Benign according to our data. Variant chr16-1202369-C-T is described in ClinVar as [Benign]. Clinvar id is 96005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202369-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.1919C>T	p.Pro640Leu	missense_variant	9/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.1919C>T	p.Pro640Leu	missense_variant	9/35	1	NM_021098.3	ENSP00000334198	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47057

AN:

152030

Hom.:

8495

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.328

Gnomad AMR

AF:

0.460

Gnomad ASJ

AF:

0.363

Gnomad EAS

AF:

0.820

Gnomad SAS

AF:

0.418

Gnomad FIN

AF:

0.325

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.271

Gnomad OTH

AF:

0.314

GnomAD3 exomes

AF:

0.386

AC:

61080

AN:

158394

Hom.:

13906

AF XY:

0.376

AC XY:

32374

AN XY:

86080

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.578

Gnomad ASJ exome

AF:

0.363

Gnomad EAS exome

AF:

0.815

Gnomad SAS exome

AF:

0.383

Gnomad FIN exome

AF:

0.316

Gnomad NFE exome

AF:

0.270

Gnomad OTH exome

AF:

0.351

GnomAD4 exome

AF:

0.295

AC:

414325

AN:

1405006

Hom.:

69712

Cov.:

AF XY:

0.297

AC XY:

206151

AN XY:

693994

show subpopulations

Gnomad4 AFR exome

AF:

0.232

Gnomad4 AMR exome

AF:

0.557

Gnomad4 ASJ exome

AF:

0.365

Gnomad4 EAS exome

AF:

0.845

Gnomad4 SAS exome

AF:

0.385

Gnomad4 FIN exome

AF:

0.325

Gnomad4 NFE exome

AF:

0.259

Gnomad4 OTH exome

AF:

0.317

GnomAD4 genome

AF:

0.309

AC:

47086

AN:

152148

Hom.:

8504

Cov.:

AF XY:

0.319

AC XY:

23701

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.232

Gnomad4 AMR

AF:

0.461

Gnomad4 ASJ

AF:

0.363

Gnomad4 EAS

AF:

0.820

Gnomad4 SAS

AF:

0.420

Gnomad4 FIN

AF:

0.325

Gnomad4 NFE

AF:

0.271

Gnomad4 OTH

AF:

0.315

Alfa

AF:

0.289

Hom.:

6086

Bravo

AF:

0.317

TwinsUK

AF:

0.249

AC:

923

ALSPAC

AF:

0.261

AC:

1004

ESP6500AA

AF:

0.194

AC:

747

ESP6500EA

AF:

0.238

AC:

1905

ExAC

AF:

0.296

AC:

31438

Asia WGS

AF:

0.551

AC:

1913

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Epilepsy, childhood absence, susceptibility to, 6

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.76

T;T;T;.

MetaRNN

Benign

0.0000012

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.9

L;.;L;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.65

N;.;N;N

REVEL

Benign

0.24

Sift

Benign

0.78

T;.;T;T

Sift4G

Benign

0.18

T;.;T;T

Polyphen

0.22

B;.;P;P

Vest4

0.23

ClinPred

0.0049

GERP RS

2.6

Varity_R

0.10

gMVP

0.32

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

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