16-56192293-G-A

Position:

• chr16-56192293-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The ENST00000262493.12(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 ENST00000262493.12 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.53

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 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000262493.12
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNAO1. . Gene score misZ 3.1919 (greater than the threshold 3.09). Trascript score misZ 4.549 (greater than threshold 3.09). GenCC has associacion of gene with 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: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.58G>A	p.Glu20Lys	missense_variant	1/9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.58G>A	p.Glu20Lys	missense_variant	1/8		NP_620073.2
GNAO1	XR_007064866.1	n.805G>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.58G>A	p.Glu20Lys	missense_variant	1/9	1	NM_020988.3	ENSP00000262493	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2022

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;.;.
MutationTaster	Benign	1.0	D;D
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

Other links and lift over

dbSNP: rs2036182701; hg19: chr16-56226205;