18-11752494-C-T

Variant names:

• chr18-11752494-C-T
• rs398122928
• NM_001369387.1:c.61C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001369387.1(GNAL):​c.61C>T​(p.Arg21*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNAL NM_001369387.1 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.92
• Publications: 4 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-11752494-C-T is Pathogenic according to our data. Variant chr18-11752494-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39972.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAL	NM_001369387.1	c.61C>T	p.Arg21*	stop_gained	Exon 1 of 12	ENST00000423027.8	NP_001356316.1
GNAL	NM_182978.4	c.377-359C>T		intron_variant	Intron 1 of 11	ENST00000334049.11	NP_892023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000423027.8	c.61C>T	p.Arg21*	stop_gained	Exon 1 of 12	1	NM_001369387.1	ENSP00000408489.2
GNAL	ENST00000535121.5	c.61C>T	p.Arg21*	stop_gained	Exon 2 of 13	1		ENSP00000439023.1
GNAL	ENST00000334049.11	c.377-359C>T		intron_variant	Intron 1 of 11	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000269162.9	c.61C>T	p.Arg21*	stop_gained	Exon 2 of 13	2		ENSP00000269162.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dystonia 25 Pathogenic:1

Jan 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.077
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		2.9
Vest4		0.51
GERP RS		2.9
PromoterAI		-0.047	Neutral
Mutation Taster		=4/196	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: rs398122928; hg19: chr18-11752493; COSMIC: COSV52333874; COSMIC: COSV52333874;