Genetic Variant NM_020988.3:c.119G>C (chr16-56192574-G-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5

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. 15/24 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

Publications

0 publications found

Variant links:

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 links:

GNAO1-DT (HGNC:27543): (GNAO1 divergent transcript)

GNAO1-DT links:

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

GNAO1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287466.

PP3

Splicing predictors support a deleterious 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 VariationId is 1802972.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020988.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNAO1	NM_020988.3	MANE Select	c.119G>C	p.Gly40Ala	missense splice_region	Exon 2 of 9	NP_066268.1
GNAO1	NM_138736.3		c.119G>C	p.Gly40Ala	missense splice_region	Exon 2 of 8	NP_620073.2
GNAO1-AS1	NR_026889.1		n.*43C>G		downstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNAO1	ENST00000262493.12	TSL:1 MANE Select	c.119G>C	p.Gly40Ala	missense splice_region	Exon 2 of 9	ENSP00000262493.6
GNAO1	ENST00000262494.13	TSL:1	c.119G>C	p.Gly40Ala	missense splice_region	Exon 2 of 8	ENSP00000262494.7
GNAO1	ENST00000638705.1	TSL:1	c.119G>C	p.Gly40Ala	missense splice_region	Exon 2 of 8	ENSP00000491223.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 17

Pathogenic:1

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.9

PhyloP100

9.6

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.83

MutPred

0.95

Loss of disorder (P = 0.1338)

MVP

0.95

MPC

2.5

ClinPred

1.0

GERP RS

4.7

PromoterAI

0.075

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over