rs398122927

chr18-11864576-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_182978.4(GNAL):c.822dup(p.Arg275ThrfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAL NM_182978.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.521

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-11864576-C-CA is Pathogenic according to our data. Variant chr18-11864576-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 39971.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAL	NM_001369387.1	c.591dup	p.Arg198ThrfsTer13	frameshift_variant	7/12	ENST00000423027.8
GNAL	NM_182978.4	c.822dup	p.Arg275ThrfsTer13	frameshift_variant	7/12	ENST00000334049.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAL	ENST00000334049.11	c.822dup	p.Arg275ThrfsTer13	frameshift_variant	7/12	1	NM_182978.4
GNAL	ENST00000423027.8	c.591dup	p.Arg198ThrfsTer13	frameshift_variant	7/12	1	NM_001369387.1	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dystonia 25 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

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: rs398122927; hg19: chr18-11864575;