16-56192588-G-T

Variant names:

• chr16-56192588-G-T
• rs869312939
• NM_020988.3:c.133G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020988.3(GNAO1):​c.133G>T​(p.Gly45*) variant causes a stop gained change involving the alteration of a 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 (★). Synonymous variant affecting the same amino acid position (i.e. G45G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 26)
• Consequence: GNAO1 NM_020988.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.69
• Publications: 0 publications found

Genes affected

GNAO1 (HGNC:4389): (G protein subunit alpha o1) The protein encoded by this gene represents the alpha subunit of the Go heterotrimeric G-protein signal-transducing complex. Defects in this gene are a cause of early-onset epileptic encephalopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

GNAO1-DT (HGNC:27543): (GNAO1 divergent transcript)

GNAO1-AS1 (HGNC:24498): (GNAO1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 16-56192588-G-T is Pathogenic according to our data. Variant chr16-56192588-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2824114.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020988.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	NM_020988.3	MANE Select	c.133G>T	p.Gly45*	stop_gained	Exon 2 of 9	NP_066268.1
	GNAO1	NM_138736.3		c.133G>T	p.Gly45*	stop_gained	Exon 2 of 8	NP_620073.2
	GNAO1-AS1	NR_026889.1		n.*29C>A		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	ENST00000262493.12	TSL:1 MANE Select	c.133G>T	p.Gly45*	stop_gained	Exon 2 of 9	ENSP00000262493.6
	GNAO1	ENST00000262494.13	TSL:1	c.133G>T	p.Gly45*	stop_gained	Exon 2 of 8	ENSP00000262494.7
	GNAO1	ENST00000638705.1	TSL:1	c.133G>T	p.Gly45*	stop_gained	Exon 2 of 8	ENSP00000491223.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Pathogenic:1

Dec 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with GNAO1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly45*) in the GNAO1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNAO1 are known to be pathogenic (PMID: 28747448).

Developmental and epileptic encephalopathy, 17;C4479569:Neurodevelopmental disorder with involuntary movements Other:1

Genomeconnect - The Bow Foundation (GNAO1)

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 01-09-2023 by Invitae. GenomeConnect-GNAO1 Registry assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	43
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.7
Vest4		0.72
GERP RS		4.7
PromoterAI		-0.048	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869312939; hg19: chr16-56226500;