rs886041766

Positions:

• chr16-56192574-G-A
• chr16-56192574-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000262493.12(GNAO1):​c.119G>A​(p.Gly40Glu) variant causes a missense, splice region 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. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G40A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAO1 ENST00000262493.12 missense, splice_region
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.60

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]

GNAO1-AS1 (HGNC:24498): (GNAO1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000262493.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56192353-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 287466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.992
• PP5: Variant 16-56192574-G-A is Pathogenic according to our data. Variant chr16-56192574-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.119G>A	p.Gly40Glu	missense_variant, splice_region_variant	2/9	ENST00000262493.12	NP_066268.1
GNAO1-AS1	NR_026889.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.119G>A	p.Gly40Glu	missense_variant, splice_region_variant	2/9	1	NM_020988.3	ENSP00000262493	P1
GNAO1-AS1	ENST00000567381.1			downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448770 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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

Jun 04, 2022

ClinVar contains an entry for this variant (Variation ID: 280589). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with epileptic encephalopathy with cerebellar atrophy (PMID: 30682224). 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 glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 40 of the GNAO1 protein (p.Gly40Glu). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2016

The G40E variant in the GNAO1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The G40E variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G40E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue, G40R, was identified as a de novo change in a female child with infantile-onset epilepsy, developmental delay, and hypotonia (Law et al., 2015). In addition, a missense variant in a nearby residue, G42R, has been reported in the Human Gene Mutation Database in association with early infantile epileptic encephalopathy 17 (Stenson et al., 2014), further supporting the functional importance of this region of the protein. We interpret G40E as a pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.5	H;.;H;H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.4	D;.;.;D;.;.
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;.;.;D;D;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.95
MutPred		0.94		Gain of disorder (P = 0.073);Gain of disorder (P = 0.073);Gain of disorder (P = 0.073);Gain of disorder (P = 0.073);Gain of disorder (P = 0.073);Gain of disorder (P = 0.073);
MVP		0.98
MPC		3.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.020		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: rs886041766; hg19: chr16-56226486;