rs59052554

Positions:

chr16-1206259-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.2759C>T(p.Thr920Met) variant causes a missense change. The variant allele was found at a frequency of 0.00259 in 1,574,574 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 9 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.89

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=0.010669082).

BP6

Variant 16-1206259-C-T is Benign according to our data. Variant chr16-1206259-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 376802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1206259-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0016 (244/152340) while in subpopulation NFE AF= 0.00241 (164/68024). AF 95% confidence interval is 0.00211. There are 2 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.2759C>T	p.Thr920Met	missense_variant	12/35	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.2759C>T	p.Thr920Met	missense_variant	12/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.2759C>T	p.Thr920Met	missense_variant	11/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.2720C>T	p.Thr907Met	missense_variant	12/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.2759C>T		non_coding_transcript_exon_variant	12/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*672C>T		non_coding_transcript_exon_variant	12/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*672C>T		3_prime_UTR_variant	12/35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00225

AC:

429

AN:

190264

Hom.:

AF XY:

0.00222

AC XY:

227

AN XY:

102242

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00380

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.000445

Gnomad NFE exome

AF:

0.00345

Gnomad OTH exome

AF:

0.00316

GnomAD4 exome

AF:

0.00269

AC:

3832

AN:

1422234

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

1840

AN XY:

703772

show subpopulations

Gnomad4 AFR exome

AF:

0.000740

Gnomad4 AMR exome

AF:

0.00109

Gnomad4 ASJ exome

AF:

0.00358

Gnomad4 EAS exome

AF:

0.000106

Gnomad4 SAS exome

AF:

0.00168

Gnomad4 FIN exome

AF:

0.000480

Gnomad4 NFE exome

AF:

0.00308

Gnomad4 OTH exome

AF:

0.00238

GnomAD4 genome

AF:

0.00160

AC:

244

AN:

152340

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00241

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.0124

Hom.:

329

Bravo

AF:

0.00168

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000947

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00228

AC:

266

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -

See cases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 03, 2020

ACMG classification criteria: BS1, BP1, BP4 -

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

0.028

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.36

T;.;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.86

D;D;D;.

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Uncertain

-0.067

MutationAssessor

Benign

-1.8

N;.;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

5.0

N;.;N;N

REVEL

Benign

0.28

Sift

Benign

1.0

T;.;T;T

Sift4G

Benign

1.0

T;.;T;T

Polyphen

0.0060

B;.;B;B

Vest4

0.29

MVP

0.43

ClinPred

0.0041

GERP RS

2.9

Varity_R

0.038

gMVP

0.66

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