rs59286323

Positions:

chr16-1213819-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.4817C>T(p.Thr1606Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,584,426 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 54 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.994

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=0.014217705).

BP6

Variant 16-1213819-C-T is Benign according to our data. Variant chr16-1213819-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 96013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1213819-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00479 (729/152210) while in subpopulation NFE AF= 0.00806 (548/67982). AF 95% confidence interval is 0.0075. There are 2 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 729 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.4817C>T	p.Thr1606Met	missense_variant	27/35	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.4817C>T	p.Thr1606Met	missense_variant	27/35	1	NM_021098.3	ENSP00000334198	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.00480

AC:

730

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00490

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00806

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00501

AC:

1010

AN:

201458

Hom.:

AF XY:

0.00519

AC XY:

566

AN XY:

109128

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.000762

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00426

Gnomad FIN exome

AF:

0.00435

Gnomad NFE exome

AF:

0.00797

Gnomad OTH exome

AF:

0.00667

GnomAD4 exome

AF:

0.00720

AC:

10312

AN:

1432216

Hom.:

Cov.:

AF XY:

0.00715

AC XY:

5073

AN XY:

709850

show subpopulations

Gnomad4 AFR exome

AF:

0.00112

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.00121

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00389

Gnomad4 FIN exome

AF:

0.00474

Gnomad4 NFE exome

AF:

0.00842

Gnomad4 OTH exome

AF:

0.00565

GnomAD4 genome

AF:

0.00479

AC:

729

AN:

152210

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

344

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00490

Gnomad4 NFE

AF:

0.00806

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00674

Hom.:

Bravo

AF:

0.00448

ESP6500AA

AF:

0.00195

AC:

ESP6500EA

AF:

0.00798

AC:

ExAC

AF:

0.00498

AC:

597

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CACNA1H: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 22, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 05, 2013

- -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 10, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

T;.;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.88

D;D;D;.

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Uncertain

0.47

MutationTaster

Benign

0.72

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.0

N;.;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.22

T;.;T;T

Sift4G

Benign

0.24

T;.;T;T

Polyphen

0.28

B;.;P;P

Vest4

0.57

MVP

0.89

ClinPred

0.013

GERP RS

3.9

Varity_R

0.086

gMVP

0.58

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