16-1204369-C-T

Position:

chr16-1204369-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.2362C>T(p.Arg788Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0917 in 1,570,246 control chromosomes in the GnomAD database, including 7,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 591 hom., cov: 33)

Exomes 𝑓: 0.094 ( 6866 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.252

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=0.00224787).

BP6

Variant 16-1204369-C-T is Benign according to our data. Variant chr16-1204369-C-T is described in ClinVar as [Benign]. Clinvar id is 96008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1204369-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 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.2362C>T	p.Arg788Cys	missense_variant	10/35	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.2362C>T	p.Arg788Cys	missense_variant	10/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.2362C>T	p.Arg788Cys	missense_variant	9/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.2323C>T	p.Arg775Cys	missense_variant	10/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.2362C>T		non_coding_transcript_exon_variant	10/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*275C>T		non_coding_transcript_exon_variant	10/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*275C>T		3_prime_UTR_variant	10/35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.0738

AC:

11231

AN:

152166

Hom.:

591

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.202

Gnomad AMR

AF:

0.0550

Gnomad ASJ

AF:

0.127

Gnomad EAS

AF:

0.105

Gnomad SAS

AF:

0.0201

Gnomad FIN

AF:

0.0885

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.0712

GnomAD3 exomes

AF:

0.0815

AC:

17344

AN:

212698

Hom.:

925

AF XY:

0.0818

AC XY:

9379

AN XY:

114708

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.0364

Gnomad ASJ exome

AF:

0.124

Gnomad EAS exome

AF:

0.104

Gnomad SAS exome

AF:

0.0182

Gnomad FIN exome

AF:

0.0915

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.0934

GnomAD4 exome

AF:

0.0936

AC:

132694

AN:

1417962

Hom.:

6866

Cov.:

AF XY:

0.0922

AC XY:

64585

AN XY:

700602

show subpopulations

Gnomad4 AFR exome

AF:

0.0143

Gnomad4 AMR exome

AF:

0.0386

Gnomad4 ASJ exome

AF:

0.126

Gnomad4 EAS exome

AF:

0.123

Gnomad4 SAS exome

AF:

0.0209

Gnomad4 FIN exome

AF:

0.0997

Gnomad4 NFE exome

AF:

0.102

Gnomad4 OTH exome

AF:

0.0866

GnomAD4 genome

AF:

0.0737

AC:

11230

AN:

152284

Hom.:

591

Cov.:

AF XY:

0.0699

AC XY:

5203

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0153

Gnomad4 AMR

AF:

0.0548

Gnomad4 ASJ

AF:

0.127

Gnomad4 EAS

AF:

0.105

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.0885

Gnomad4 NFE

AF:

0.109

Gnomad4 OTH

AF:

0.0700

Alfa

AF:

0.0974

Hom.:

626

Bravo

AF:

0.0694

TwinsUK

AF:

0.106

AC:

393

ALSPAC

AF:

0.100

AC:

386

ESP6500AA

AF:

0.0154

AC:

ESP6500EA

AF:

0.103

AC:

876

ExAC

AF:

0.0821

AC:

9851

Asia WGS

AF:

0.0720

AC:

250

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2019	This variant is associated with the following publications: (PMID: 17696120, 28933792) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 03, 2013

- -

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

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.058

LIST_S2

Uncertain

0.89

D;D;D;.

MetaRNN

Benign

0.0022

T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.2

M;.;M;M

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-4.7

D;.;D;D

REVEL

Uncertain

0.36

Sift

Benign

0.033

D;.;D;D

Sift4G

Uncertain

0.039

D;.;D;D

Polyphen

0.018

B;.;B;B

Vest4

0.28

ClinPred

0.033

GERP RS

0.51

Varity_R

0.21

gMVP

0.54

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