Genetic Variant GNAL:p.Gly16Arg (chr18-11689609-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_182978.4(GNAL):c.46G>C(p.Gly16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000588 in 1,191,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

GNAL
NM_182978.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22131729).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAL	NM_182978.4 link	c.46G>C	p.Gly16Arg	missense_variant	Exon 1 of 12	ENST00000334049.11	NP_892023.1	P38405-2
GNAL	XM_006722324.4 link	c.46G>C	p.Gly16Arg	missense_variant	Exon 1 of 6		XP_006722387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11 link	c.46G>C	p.Gly16Arg	missense_variant	Exon 1 of 12	1	NM_182978.4	ENSP00000334051.5		P38405-2
GNAL	ENST00000585590.1 link	n.-81G>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000588

AC:

AN:

1191250

Hom.:

Cov.:

AF XY:

0.00000518

AC XY:

AN XY:

578680

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23280

American (AMR)

AF:

0.00

AC:

AN:

9220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15940

East Asian (EAS)

AF:

0.00

AC:

AN:

26726

South Asian (SAS)

AF:

0.00

AC:

AN:

46196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3300

European-Non Finnish (NFE)

AF:

0.00000707

AC:

AN:

989700

Other (OTH)

AF:

0.00

AC:

AN:

48648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dystonic disorder

Uncertain:1

Aug 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.58

PhyloP100

2.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.090

REVEL

Benign

0.24

Sift

Benign

0.046

Sift4G

Benign

0.12

Vest4

0.12

MutPred

0.17

Loss of relative solvent accessibility (P = 0.0404);

MVP

0.33

MPC

1.5

ClinPred

0.66

GERP RS

3.4

PromoterAI

-0.021

Neutral

(source)

gMVP

0.14

Mutation Taster

=95/5

polymorphism

(source)

Splicing

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over