chr16-1208033-G-T

Position:

chr16-1208033-G-T

Variant summary

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

The ENST00000348261.11(CACNA1H):c.3175G>T(p.Ala1059Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00933 in 1,606,222 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1059A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 94 hom. )

Consequence

CACNA1H
ENST00000348261.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.90

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=0.007585913).

BP6

Variant 16-1208033-G-T is Benign according to our data. Variant chr16-1208033-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 460081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1208033-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00705 (1073/152182) while in subpopulation AMR AF= 0.0112 (172/15292). AF 95% confidence interval is 0.00987. There are 7 homozygotes in gnomad4. There are 495 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1073 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.3175G>T	p.Ala1059Ser	missense_variant	16/35	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.3175G>T	p.Ala1059Ser	missense_variant	16/35	1	NM_021098.3	ENSP00000334198	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.00707

AC:

1075

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00725

AC:

1707

AN:

235422

Hom.:

AF XY:

0.00757

AC XY:

970

AN XY:

128146

show subpopulations

Gnomad AFR exome

AF:

0.00206

Gnomad AMR exome

AF:

0.00636

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00442

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.00957

AC:

13920

AN:

1454040

Hom.:

Cov.:

AF XY:

0.00945

AC XY:

6827

AN XY:

722570

show subpopulations

Gnomad4 AFR exome

AF:

0.00294

Gnomad4 AMR exome

AF:

0.00660

Gnomad4 ASJ exome

AF:

0.0157

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00394

Gnomad4 FIN exome

AF:

0.000928

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.00705

AC:

1073

AN:

152182

Hom.:

Cov.:

AF XY:

0.00665

AC XY:

495

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.0112

Gnomad4 ASJ

AF:

0.0208

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.0100

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00953

Hom.:

Bravo

AF:

0.00753

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00247

AC:

ESP6500EA

AF:

0.0100

AC:

ExAC

AF:

0.00649

AC:

783

Asia WGS

AF:

0.00433

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:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CACNA1H: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2020	This variant is associated with the following publications: (PMID: 17696120, 25525159, 26706850) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 06, 2019	- -

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

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-0.042

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.76

T;T;T;.

MetaRNN

Benign

0.0076

T;T;T;T

MetaSVM

Uncertain

-0.053

MutationAssessor

Benign

1.8

L;.;L;L

MutationTaster

Benign

0.89

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.0

N;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.56

T;.;T;T

Sift4G

Benign

0.66

T;.;T;T

Polyphen

0.91

P;.;P;P

Vest4

0.47

MVP

0.88

ClinPred

0.022

GERP RS

3.0

Varity_R

0.081

gMVP

0.38

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