16-56336824-C-G

Variant names:

• chr16-56336824-C-G
• NM_020988.3:c.687C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. 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 (★).

• 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 Likely_pathogenic. Variant got 9 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, 0.971
• 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 rank	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.687C>G	p.Ser229Arg	missense_variant	Exon 6 of 9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.687C>G	p.Ser229Arg	missense_variant	Exon 6 of 8		NP_620073.2
GNAO1	XM_011523003.4	c.561C>G	p.Ser187Arg	missense_variant	Exon 6 of 9		XP_011521305.1
GNAO1	XR_007064866.1	n.1434C>G		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.687C>G	p.Ser229Arg	missense_variant	Exon 6 of 9	1	NM_020988.3	ENSP00000262493.6

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

Feb 03, 2021

Pediatric Department, Peking University First Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 17 Pathogenic:1

Aug 14, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Pathogenic	0.98	.;D;D;D;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;.;.
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;