Variant rs79011683 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_StrongBP6_Moderate

The NM_000069.3(CACNA1S):c.4346T>G(p.Val1449Gly) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1449M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter U:1B:2

Conservation

PhyloP100: 9.30

Variant links:

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

CACNA1S links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, MetaRNN, MutationTaster, PrimateAI was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0042477846).

BP6

Variant 1-201048677-A-C is Benign according to our data. Variant chr1-201048677-A-C is described in ClinVar as [Benign]. Clinvar id is 294720.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.4346T>G	p.Val1449Gly	missense_variant	36/44	ENST00000362061.4
CACNA1S	XM_005245478.4 linkuse as main transcript	c.4289T>G	p.Val1430Gly	missense_variant	35/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.4346T>G	p.Val1449Gly	missense_variant	36/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

148

AN:

151518

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00204

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.00240

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0206

AC:

29743

AN:

1441400

Hom.:

Cov.:

AF XY:

0.0246

AC XY:

17629

AN XY:

715304

show subpopulations

Gnomad4 AFR exome

AF:

0.0248

Gnomad4 AMR exome

AF:

0.0934

Gnomad4 ASJ exome

AF:

0.0401

Gnomad4 EAS exome

AF:

0.0428

Gnomad4 SAS exome

AF:

0.0477

Gnomad4 FIN exome

AF:

0.0848

Gnomad4 NFE exome

AF:

0.0118

Gnomad4 OTH exome

AF:

0.0154

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000989

AC:

150

AN:

151620

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

AN XY:

74050

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00204

Gnomad4 EAS

AF:

0.000389

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00181

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.0873

Hom.:

ExAC

AF:

0.220

AC:

25067

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 5

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Dec 04, 2015

- -

Hypokalemic periodic paralysis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Malignant hyperthermia of anesthesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Pathogenic

3.3

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

.;D

Vest4

0.21

MPC

0.56

ClinPred

0.066

GERP RS

5.2

Varity_R

0.91

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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