rs1297388989

Variant names:

• chr16-56336741-G-A
• rs1297388989
• NM_020988.3:c.604G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-56336741-G-A
• chr16-56336741-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_020988.3(GNAO1):​c.604G>A​(p.Val202Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V202V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.99
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• movement disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• neurodevelopmental disorder with involuntary movements

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 17 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 16-56336741-G-A is Pathogenic according to our data. Variant chr16-56336741-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 545591.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	NM_020988.3	MANE Select	c.604G>A	p.Val202Ile	missense	Exon 6 of 9	NP_066268.1	P09471-1
	GNAO1	NM_138736.3		c.604G>A	p.Val202Ile	missense	Exon 6 of 8	NP_620073.2	P09471-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	ENST00000262493.12	TSL:1 MANE Select	c.604G>A	p.Val202Ile	missense	Exon 6 of 9	ENSP00000262493.6	P09471-1
	GNAO1	ENST00000262494.13	TSL:1	c.604G>A	p.Val202Ile	missense	Exon 6 of 8	ENSP00000262494.7	P09471-2
	GNAO1	ENST00000638705.1	TSL:1	c.604G>A	p.Val202Ile	missense	Exon 6 of 8	ENSP00000491223.1	P09471-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459214 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725786

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111238

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	GNAO1-related disorder (1)
-	1	-	Neurodevelopmental disorder with involuntary movements (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.95	N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.52
MutPred		0.86		Gain of catalytic residue at V202 (P = 0.0681)
MVP		0.89
MPC		2.4
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.10	Neutral
Varity_R		0.81
gMVP		0.86

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

Other links and lift over

dbSNP: rs1297388989; hg19: chr16-56370653;