16-56192302-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_020988.3(GNAO1):​c.67C>T​(p.Leu23Phe) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

GNAO1
NM_020988.3 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.66
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, 0.958

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNAO1NM_020988.3 linkc.67C>T p.Leu23Phe missense_variant Exon 1 of 9 ENST00000262493.12 NP_066268.1 P09471-1Q8N6I9B3KP89
GNAO1NM_138736.3 linkc.67C>T p.Leu23Phe missense_variant Exon 1 of 8 NP_620073.2 P09471-2Q8N6I9B3KP89Q6AWC5
GNAO1XR_007064866.1 linkn.814C>T 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.67C>T p.Leu23Phe 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: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Oct 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNAO1 protein function. 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 replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 23 of the GNAO1 protein (p.Leu23Phe). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;.;D;.;T;.
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
.;D;D;D;D;D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.0
H;.;H;H;.;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-2.5
D;.;.;D;.;.
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0010
D;.;.;D;.;.
Sift4G
Uncertain
0.0040
D;.;.;D;D;.
Polyphen
1.0
D;.;D;D;.;.
Vest4
0.50
MutPred
0.86
Gain of methylation at K24 (P = 0.0377);Gain of methylation at K24 (P = 0.0377);Gain of methylation at K24 (P = 0.0377);Gain of methylation at K24 (P = 0.0377);Gain of methylation at K24 (P = 0.0377);Gain of methylation at K24 (P = 0.0377);
MVP
0.87
MPC
2.8
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.93
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: chr16-56226214; API