16-56336824-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_020988.3(GNAO1):c.687C>G(p.Ser229Arg) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. S229S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.550

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_020988.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GNAO1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 16-56336824-C-G is Pathogenic according to our data. Variant chr16-56336824-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1012171.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.687C>G	p.Ser229Arg	missense_variant	6/9	ENST00000262493.12
GNAO1	NM_138736.3	c.687C>G	p.Ser229Arg	missense_variant	6/8
GNAO1	XM_011523003.4	c.561C>G	p.Ser187Arg	missense_variant	6/9
GNAO1	XR_007064866.1	n.1434C>G		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.687C>G	p.Ser229Arg	missense_variant	6/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 17;C4479569:Neurodevelopmental disorder with involuntary movements Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Pediatric Department, Peking University First Hospital

Feb 03, 2021

- -

Developmental and epileptic encephalopathy, 17 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 14, 2023

Criteria applied: PS2_STR,PM1,PS4_SUP,PM2_SUP,PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.4	H;H;H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.7	D;.;D;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Pathogenic	0.0	D;.;D;.;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.97
MutPred		0.87		Loss of glycosylation at S229 (P = 0.08);Loss of glycosylation at S229 (P = 0.08);Loss of glycosylation at S229 (P = 0.08);.;.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.98
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: chr16-56370736;