rs398122923

Positions:

• chr18-11824933-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.96

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAL	NM_182978.4	c.640G>A	p.Val214Met	missense_variant	5/12	ENST00000334049.11	NP_892023.1
GNAL	NM_001369387.1	c.409G>A	p.Val137Met	missense_variant	5/12	ENST00000423027.8	NP_001356316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11	c.640G>A	p.Val214Met	missense_variant	5/12	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000423027.8	c.409G>A	p.Val137Met	missense_variant	5/12	1	NM_001369387.1	ENSP00000408489.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1431776 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 713558

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 25 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 20, 2024

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	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	31
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	D
LIST_S2	Uncertain	0.97	D;.;.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.54	.;N;N;N;.;.
PrimateAI	Uncertain	0.78	T
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	D
GERP RS		5.7
Varity_R		0.27
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs398122923; hg19: chr18-11824932;