chr16-1215315-G-A

Position:

chr16-1215315-G-A

Variant summary

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

The ENST00000348261.11(CACNA1H):c.5113G>A(p.Ala1705Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,611,068 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts 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. A1705A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0057 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 37 hom. )

Consequence

CACNA1H
ENST00000348261.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 9.78

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=0.011093318).

BP6

Variant 16-1215315-G-A is Benign according to our data. Variant chr16-1215315-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1215315-G-A is described in Lovd as [Benign]. Variant chr16-1215315-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0057 (869/152328) while in subpopulation NFE AF= 0.00858 (584/68026). AF 95% confidence interval is 0.00801. There are 5 homozygotes in gnomad4. There are 374 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 869 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.5113G>A	p.Ala1705Thr	missense_variant	29/35	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.5113G>A	p.Ala1705Thr	missense_variant	29/35	1	NM_021098.3	ENSP00000334198	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.00570

AC:

868

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00851

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00858

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00556

AC:

1356

AN:

243960

Hom.:

AF XY:

0.00551

AC XY:

731

AN XY:

132768

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00424

Gnomad ASJ exome

AF:

0.00871

Gnomad EAS exome

AF:

0.0000562

Gnomad SAS exome

AF:

0.000300

Gnomad FIN exome

AF:

0.00557

Gnomad NFE exome

AF:

0.00835

Gnomad OTH exome

AF:

0.00941

GnomAD4 exome

AF:

0.00731

AC:

10664

AN:

1458740

Hom.:

Cov.:

AF XY:

0.00711

AC XY:

5161

AN XY:

725390

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.00508

Gnomad4 ASJ exome

AF:

0.00891

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000280

Gnomad4 FIN exome

AF:

0.00595

Gnomad4 NFE exome

AF:

0.00844

Gnomad4 OTH exome

AF:

0.00718

GnomAD4 genome

AF:

0.00570

AC:

869

AN:

152328

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

374

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.00850

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00442

Gnomad4 NFE

AF:

0.00858

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00750

Hom.:

Bravo

AF:

0.00630

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00161

AC:

ESP6500EA

AF:

0.00925

AC:

ExAC

AF:

0.00554

AC:

670

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 22, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CACNA1H: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 31, 2023

- -

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

0.23

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;.;.;.

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Pathogenic

0.92

MutationAssessor

Benign

1.4

L;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.9

D;.;D;D

REVEL

Uncertain

0.61

Sift

Benign

0.060

T;.;T;T

Sift4G

Uncertain

0.039

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.64

MVP

0.95

ClinPred

0.022

GERP RS

4.0

Varity_R

0.32

gMVP

0.69

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