NM_020988.3:c.119G>C

Variant names:

• chr16-56192574-G-C
• NM_020988.3:c.119G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_020988.3(GNAO1):​c.119G>C​(p.Gly40Ala) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G40R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 26)
• Consequence: GNAO1 NM_020988.3 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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:):

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest G1 motif (size 13) in uniprot entity GNAO_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_020988.3
• 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 Lovd as [Likely_pathogenic].
• 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 16-56192574-G-C is Pathogenic according to our data. Variant chr16-56192574-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1802972.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.119G>C	p.Gly40Ala	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000262493.12	NP_066268.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.119G>C	p.Gly40Ala	missense_variant, splice_region_variant	Exon 2 of 9	1	NM_020988.3	ENSP00000262493.6

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 17 Pathogenic:1

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Key Laboratory of Neurobehavioral Science for Children, Children's Hospital Affiliated of Zhengzhou University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.9	H;.;H;H;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.8	D;.;.;D;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;.;.;D;.;.
Sift4G	Uncertain	0.0020	D;.;.;D;T;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.83
MutPred		0.95		Loss of disorder (P = 0.1338);Loss of disorder (P = 0.1338);Loss of disorder (P = 0.1338);Loss of disorder (P = 0.1338);Loss of disorder (P = 0.1338);Loss of disorder (P = 0.1338);
MVP		0.95
MPC		2.5
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.010		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: chr16-56226486; COSMIC: COSV52618464; COSMIC: COSV52618464;