dbSNP rs398122923: GNAL:p.Val214Met (chr18-11824933-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182978.4(GNAL):c.640G>A(p.Val214Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAL
NM_182978.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 3.96

Publications

8 publications found

Variant links:

Genes affected

GNAL (HGNC:4388): (G protein subunit alpha L) This gene encodes a stimulatory G protein alpha subunit which mediates odorant signaling in the olfactory epithelium. This protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. Mutations in this gene have been associated with dystonia 25 and this gene is located in a susceptibility region for bipolar disorder and schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

GNAL Gene-Disease associations (from GenCC):

dystonia 25
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

GNAL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAL	NM_182978.4 link	c.640G>A	p.Val214Met	missense_variant	Exon 5 of 12	ENST00000334049.11	NP_892023.1	P38405-2
GNAL	NM_001369387.1 link	c.409G>A	p.Val137Met	missense_variant	Exon 5 of 12	ENST00000423027.8	NP_001356316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11 link	c.640G>A	p.Val214Met	missense_variant	Exon 5 of 12	1	NM_182978.4	ENSP00000334051.5		P38405-2
GNAL	ENST00000423027.8 link	c.409G>A	p.Val137Met	missense_variant	Exon 5 of 12	1	NM_001369387.1	ENSP00000408489.2		P38405-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1431776

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713558

African (AFR)

AF:

0.00

AC:

AN:

32490

American (AMR)

AF:

0.00

AC:

AN:

43206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25874

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.00

AC:

AN:

83832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088452

Other (OTH)

AF:

0.00

AC:

AN:

59374

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dystonia 25

Pathogenic:1

Jan 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Feb 20, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that the variant results in little to modest effect on the protein (PMID: 30021154); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26725140, Giri2017[Thesis], 29948482, 24136457, 23775978, 24952478, 30021154, 23222958) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.52

.;D;D;D;T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;.;.;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.70

D;D;D;D;D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.54

.;N;N;N;.;.

PhyloP100

4.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.5

N;N;N;N;.;.

REVEL

Uncertain

0.63

Sift

Benign

0.36

T;T;T;T;.;.

Sift4G

Benign

0.35

T;T;T;T;T;T

Polyphen

0.40

.;B;B;B;.;.

Vest4

0.47

MutPred

0.59

.;Gain of ubiquitination at K139 (P = 0.1064);Gain of ubiquitination at K139 (P = 0.1064);Gain of ubiquitination at K139 (P = 0.1064);.;.;

MVP

0.92

MPC

2.4

ClinPred

0.78

GERP RS

5.7

Varity_R

0.27

gMVP

0.70

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over