chr16-56351396-G-A

Variant names:

• chr16-56351396-G-A
• rs797044951
• NM_020988.3:c.736G>A

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1 PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020988.3(GNAO1):​c.736G>A​(p.Glu246Lys) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000321739: Cells transfected with the E246K variant exhibited lower protein levels compared to wild-type, and functional studies demonstrated a gain-of-function effect for the E246K variant (PMID:28747448)" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E246G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 10.0
• Publications: 38 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 26 ACMG points.

• PS1: Transcript NM_020988.3 (GNAO1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321739: Cells transfected with the E246K variant exhibited lower protein levels compared to wild-type, and functional studies demonstrated a gain-of-function effect for the E246K variant (PMID: 28747448); SCV002058168: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 28747448).; SCV004801504: Functional studies demonstrated when the p.Glu246Lys variant was expressed in HEK293T cells, it exhibited increased potency for α2A AR–mediated cAMP inhibition consistent with a gain-of-function mechanism (Feng et al. 2017).; SCV002241963: Experimental studies have shown that this missense change affects GNAO1 function (PMID: 28747448).; SCV004814153: Functional studies found that when the p.Glu246Lys variant expressed in HEK293T cells, it exhibited increased potency for alpha-2A AR-mediated cAMP inhibition consistent with a gain-of-function mechanism (Feng et al. 2017).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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 chr16-56351397-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 427730.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 16-56351396-G-A is Pathogenic according to our data. Variant chr16-56351396-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208777.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.736G>A	p.Glu246Lys	missense	Exon 7 of 9	NP_066268.1	P09471-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	ENST00000262493.12	TSL:1 MANE Select	c.736G>A	p.Glu246Lys	missense	Exon 7 of 9	ENSP00000262493.6	P09471-1
	GNAO1	ENST00000638705.1	TSL:1	c.736G>A	p.Glu246Lys	missense	Exon 7 of 8	ENSP00000491223.1	P09471-1
	GNAO1	ENST00000873096.1		c.760G>A	p.Glu254Lys	missense	Exon 7 of 9	ENSP00000543155.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Neurodevelopmental disorder with involuntary movements (4)
3	-	-	not provided (3)
1	-	-	Abnormality of the nervous system (1)
1	-	-	Developmental and epileptic encephalopathy (1)
1	-	-	Developmental delay (1)
1	-	-	GNAO1-related developmental delay-seizures-movement disorder spectrum (1)
1	-	-	Inborn genetic diseases (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	0.48
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		10
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.90		Gain of ubiquitination at E246 (P = 0.023)
MVP		0.97
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
Mutation Taster		=3/97	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: rs797044951; hg19: chr16-56385308;