rs398122923

Variant names:

• chr18-11824933-G-A
• rs398122923
• NM_182978.4:c.640G>A

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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.96
• Publications: 8 publications found

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182978.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	NM_182978.4	MANE Select	c.640G>A	p.Val214Met	missense	Exon 5 of 12	NP_892023.1	P38405-2
	GNAL	NM_001369387.1	MANE Plus Clinical	c.409G>A	p.Val137Met	missense	Exon 5 of 12	NP_001356316.1	A8K1Y9
	GNAL	NM_001142339.3		c.409G>A	p.Val137Met	missense	Exon 6 of 13	NP_001135811.1	A8K1Y9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	ENST00000334049.11	TSL:1 MANE Select	c.640G>A	p.Val214Met	missense	Exon 5 of 12	ENSP00000334051.5	P38405-2
	GNAL	ENST00000423027.8	TSL:1 MANE Plus Clinical	c.409G>A	p.Val137Met	missense	Exon 5 of 12	ENSP00000408489.2	P38405-1
	GNAL	ENST00000535121.5	TSL:1	c.409G>A	p.Val137Met	missense	Exon 6 of 13	ENSP00000439023.1	P38405-1

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

African (AFR) AF: 0.00 AC: 0 AN: 32490

American (AMR) AF: 0.00 AC: 0 AN: 43206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 83832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088452

Other (OTH) AF: 0.00 AC: 0 AN: 59374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Dystonia 25 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.54	N
PhyloP100		4.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.63
Sift	Benign	0.36	T
Sift4G	Benign	0.35	T
Polyphen		0.40	B
Vest4		0.47
MutPred		0.59		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398122923; hg19: chr18-11824932;