rs57315342

Positions:

chr16-1210783-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(CACNA1H):c.4039-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,599,932 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 3 hom., cov: 35)

Exomes 𝑓: 0.0035 ( 36 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001501

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -1.75

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 16-1210783-G-A is Benign according to our data. Variant chr16-1210783-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460106.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=3}. Variant chr16-1210783-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00293 (446/152358) while in subpopulation SAS AF= 0.00435 (21/4832). AF 95% confidence interval is 0.00312. There are 3 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High AC in GnomAd4 at 446 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.4039-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.4039-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021098.3	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

446

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00348

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00359

AC:

849

AN:

236414

Hom.:

AF XY:

0.00378

AC XY:

491

AN XY:

129874

show subpopulations

Gnomad AFR exome

AF:

0.000332

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.0298

Gnomad EAS exome

AF:

0.0000561

Gnomad SAS exome

AF:

0.00354

Gnomad FIN exome

AF:

0.000154

Gnomad NFE exome

AF:

0.00316

Gnomad OTH exome

AF:

0.00644

GnomAD4 exome

AF:

0.00355

AC:

5133

AN:

1447574

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

2628

AN XY:

720622

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.0327

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00372

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00315

Gnomad4 OTH exome

AF:

0.00475

GnomAD4 genome

AF:

0.00293

AC:

446

AN:

152358

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

203

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.0331

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00348

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00554

Hom.:

Bravo

AF:

0.00289

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CACNA1H: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2018	- -

CACNA1H-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.13

DANN

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.020

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