16-56192292-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_020988.3(GNAO1):c.57T>G(p.Ile19Met) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I19N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.72

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GNAO1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 16-56192292-T-G is Pathogenic according to our data. Variant chr16-56192292-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2500270.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.57T>G	p.Ile19Met	missense_variant	1/9	ENST00000262493.12
GNAO1	NM_138736.3	c.57T>G	p.Ile19Met	missense_variant	1/8
GNAO1	XR_007064866.1	n.804T>G		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.57T>G	p.Ile19Met	missense_variant	1/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Feb 09, 2023

- -

Developmental and epileptic encephalopathy, 17 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Feb 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.;D;.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.0	H;.;H;H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N;.;.;N;.;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;.;.;D;D;.
Polyphen		0.98	D;.;D;D;.;.
Vest4		0.66
MutPred		0.75		Gain of ubiquitination at K21 (P = 0.0501);Gain of ubiquitination at K21 (P = 0.0501);Gain of ubiquitination at K21 (P = 0.0501);Gain of ubiquitination at K21 (P = 0.0501);Gain of ubiquitination at K21 (P = 0.0501);Gain of ubiquitination at K21 (P = 0.0501);
MVP		0.88
MPC		2.6
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.96
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-56226204;