16-56192292-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_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 (★).

Frequency

Genomes: not found (cov: 31)

Consequence

GNAO1
NM_020988.3 missense

Scores

9
7
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.72
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the GNAO1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 70 curated pathogenic missense variants (we use a threshold of 10). The gene has 43 curated benign missense variants. Gene score misZ: 3.1919 (above the threshold of 3.09). Trascript score misZ: 4.549 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 17, neurodevelopmental disorder with involuntary movements, developmental and epileptic encephalopathy, movement disorder.
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 rank MANE Protein UniProt
GNAO1NM_020988.3 linkc.57T>G p.Ile19Met missense_variant Exon 1 of 9 ENST00000262493.12 NP_066268.1 P09471-1Q8N6I9B3KP89
GNAO1NM_138736.3 linkc.57T>G p.Ile19Met missense_variant Exon 1 of 8 NP_620073.2 P09471-2Q8N6I9B3KP89Q6AWC5
GNAO1XR_007064866.1 linkn.804T>G non_coding_transcript_exon_variant Exon 1 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNAO1ENST00000262493.12 linkc.57T>G p.Ile19Met missense_variant Exon 1 of 9 1 NM_020988.3 ENSP00000262493.6 P09471-1

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
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 17;C4479569:Neurodevelopmental disorder with involuntary movements Pathogenic:1
Feb 09, 2023
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 17 Pathogenic:1
Feb 09, 2023
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
LIST_S2
Benign
0.81
.;T;T;T;T;T
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;.;.
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; API