16-56336741-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_020988.3(GNAO1):c.604G>C(p.Val202Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V202I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr16-56336741-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 545591.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, GNAO1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.604G>C	p.Val202Leu	missense_variant	6/9	ENST00000262493.12
GNAO1	NM_138736.3	c.604G>C	p.Val202Leu	missense_variant	6/8
GNAO1	XM_011523003.4	c.478G>C	p.Val160Leu	missense_variant	6/9
GNAO1	XR_007064866.1	n.1351G>C		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.604G>C	p.Val202Leu	missense_variant	6/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.5	M;M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D;.;D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.052	T;.;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.87
MutPred		0.88		Loss of MoRF binding (P = 0.1258);Loss of MoRF binding (P = 0.1258);Loss of MoRF binding (P = 0.1258);.;
MVP		0.96
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs1297388989; hg19: chr16-56370653;