rs759668583

chr16-1209249-G-Achr16-1209249-G-Cchr16-1209249-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_021098.3(CACNA1H):c.3581G>A(p.Arg1194Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000661 in 1,544,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1194W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000061 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.125

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023409247).

BP6

Variant 16-1209249-G-A is Benign according to our data. Variant chr16-1209249-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529585.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}. Variant chr16-1209249-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.3581G>A	p.Arg1194Gln	missense_variant	17/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.3581G>A	p.Arg1194Gln	missense_variant	17/35	1	NM_021098.3	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000572

AC:

AN:

139912

Hom.:

AF XY:

0.0000389

AC XY:

AN XY:

77146

show subpopulations

Gnomad AFR exome

AF:

0.000166

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000377

Gnomad SAS exome

AF:

0.0000441

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000374

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000611

AC:

AN:

1392070

Hom.:

Cov.:

AF XY:

0.0000655

AC XY:

AN XY:

687412

show subpopulations

Gnomad4 AFR exome

AF:

0.000193

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000281

Gnomad4 SAS exome

AF:

0.0000251

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000574

Gnomad4 OTH exome

AF:

0.0000865

GnomAD4 genome

AF:

0.000112

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000384

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000868

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2022

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.3581G>A (p.R1194Q) alteration is located in exon 17 (coding exon 16) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 3581, causing the arginine (R) at amino acid position 1194 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

-0.040

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.79

T;T;T;.

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.023

T;T;T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.1

M;.;M;M

MutationTaster

Benign

0.92

N;N;N

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.5

N;.;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.12

T;.;T;T

Sift4G

Benign

0.061

T;.;T;T

Polyphen

0.015

B;.;B;B

Vest4

0.31

MutPred

0.23

Gain of glycosylation at T1191 (P = 0.102);.;Gain of glycosylation at T1191 (P = 0.102);Gain of glycosylation at T1191 (P = 0.102);

MVP

0.87

ClinPred

0.030

GERP RS

3.1

Varity_R

0.12

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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