Genetic Variant GNAO1:p.Ser6Ile (chr16-56192252-G-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_020988.3(GNAO1):c.17G>T(p.Ser6Ile) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAO1
NM_020988.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.53

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 16-56192252-G-T is Pathogenic according to our data. Variant chr16-56192252-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1802165.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 link	c.17G>T	p.Ser6Ile	missense_variant	Exon 1 of 9	ENST00000262493.12	NP_066268.1	P09471-1Q8N6I9B3KP89
GNAO1	NM_138736.3 link	c.17G>T	p.Ser6Ile	missense_variant	Exon 1 of 8		NP_620073.2	P09471-2Q8N6I9B3KP89Q6AWC5
GNAO1	XR_007064866.1 link	n.764G>T		non_coding_transcript_exon_variant	Exon 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12 link	c.17G>T	p.Ser6Ile	missense_variant	Exon 1 of 9	1	NM_020988.3	ENSP00000262493.6		P09471-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1444788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718652

African (AFR)

AF:

0.00

AC:

AN:

33144

American (AMR)

AF:

0.00

AC:

AN:

43872

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25868

East Asian (EAS)

AF:

0.00

AC:

AN:

39274

South Asian (SAS)

AF:

0.00

AC:

AN:

84568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100916

Other (OTH)

AF:

0.00

AC:

AN:

59792

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;.;D;.;T;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;D;D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

H;.;H;H;.;.

PhyloP100

9.5

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.1

D;.;.;D;.;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.;.;D;.;.

Sift4G

Pathogenic

0.0

D;.;.;D;D;.

Polyphen

1.0

D;.;D;D;.;.

Vest4

0.52

MutPred

0.76

Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);

MVP

0.90

MPC

2.9

ClinPred

1.0

GERP RS

4.8

PromoterAI

0.058

Neutral

(source)

Varity_R

0.93

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: 6

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over