16-56192293-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_020988.3(GNAO1):​c.58G>A​(p.Glu20Lys) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

GNAO1
NM_020988.3 missense

Scores

10
7
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 9.53
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 6 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, 0.879
PP5
Variant 16-56192293-G-A is Pathogenic according to our data. Variant chr16-56192293-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 946388.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNAO1NM_020988.3 linkc.58G>A p.Glu20Lys missense_variant Exon 1 of 9 ENST00000262493.12 NP_066268.1 P09471-1Q8N6I9B3KP89
GNAO1NM_138736.3 linkc.58G>A p.Glu20Lys missense_variant Exon 1 of 8 NP_620073.2 P09471-2Q8N6I9B3KP89Q6AWC5
GNAO1XR_007064866.1 linkn.805G>A 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.58G>A p.Glu20Lys 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: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Feb 01, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 946388). This missense change has been observed in individual(s) with clinical features of GNAO1-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 20 of the GNAO1 protein (p.Glu20Lys). -

Inborn genetic diseases Uncertain:1
Aug 22, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.58G>A (p.E20K) alteration is located in exon 1 (coding exon 1) of the GNAO1 gene. This alteration results from a G to A substitution at nucleotide position 58, causing the glutamic acid (E) at amino acid position 20 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.91
D;.;D;.;T;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
.;D;D;D;D;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Uncertain
2.6
M;.;M;M;.;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
-2.3
N;.;.;N;.;.
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0020
D;.;.;D;.;.
Sift4G
Uncertain
0.022
D;.;.;D;D;.
Polyphen
0.78
P;.;P;P;.;.
Vest4
0.44
MutPred
0.62
Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);
MVP
0.89
MPC
2.2
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.92
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2036182701; hg19: chr16-56226205; API