16-56336762-C-T

Variant names:

• chr16-56336762-C-T
• rs886039494
• NM_020988.3:c.625C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020988.3(GNAO1):​c.625C>T​(p.Arg209Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R209G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 4.91
• Publications: 45 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr16-56336762-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 427726.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 16-56336762-C-T is Pathogenic according to our data. Variant chr16-56336762-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 265350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	NM_020988.3	MANE Select	c.625C>T	p.Arg209Cys	missense	Exon 6 of 9	NP_066268.1	P09471-1
	GNAO1	NM_138736.3		c.625C>T	p.Arg209Cys	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.625C>T	p.Arg209Cys	missense	Exon 6 of 9	ENSP00000262493.6	P09471-1
	GNAO1	ENST00000262494.13	TSL:1	c.625C>T	p.Arg209Cys	missense	Exon 6 of 8	ENSP00000262494.7	P09471-2
	GNAO1	ENST00000638705.1	TSL:1	c.625C>T	p.Arg209Cys	missense	Exon 6 of 8	ENSP00000491223.1	P09471-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000432 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Neurodevelopmental disorder with involuntary movements (6)
3	-	-	not provided (3)
1	-	-	Developmental and epileptic encephalopathy (1)
1	-	-	Developmental and epileptic encephalopathy, 17 (1)
1	-	-	GNAO1-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Movement disorder (1)
-	-	-	Developmental and epileptic encephalopathy, 17;C4479569:Neurodevelopmental disorder with involuntary movements (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		4.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Loss of disorder (P = 0.01)
MVP		0.97
MPC		3.2
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.045	Neutral
Varity_R		0.94
gMVP		0.99
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs886039494; hg19: chr16-56370674; COSMIC: COSV52619324; COSMIC: COSV52619324;