rs398122928

Positions:

• chr18-11752494-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001369387.1(GNAL):​c.61C>T​(p.Arg21Ter) 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

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 Likely_pathogenic. Variant got 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. Fraction of 0.947 CDS is truncated, and there are 0 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 id is 39972.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAL	NM_001369387.1	c.61C>T	p.Arg21Ter	stop_gained	1/12	ENST00000423027.8	NP_001356316.1
GNAL	NM_182978.4	c.377-359C>T		intron_variant		ENST00000334049.11	NP_892023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000423027.8	c.61C>T	p.Arg21Ter	stop_gained	1/12	1	NM_001369387.1	ENSP00000408489	P1
GNAL	ENST00000535121.5	c.61C>T	p.Arg21Ter	stop_gained	2/13	1		ENSP00000439023	P1
GNAL	ENST00000334049.11	c.377-359C>T		intron_variant		1	NM_182978.4	ENSP00000334051
GNAL	ENST00000269162.9	c.61C>T	p.Arg21Ter	stop_gained	2/13	2		ENSP00000269162	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

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
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.51
GERP RS		2.9

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: rs398122928; hg19: chr18-11752493; COSMIC: COSV52333874; COSMIC: COSV52333874;