16-56328665-G-C

Variant names:

• chr16-56328665-G-C
• rs956210011
• NM_020988.3:c.338G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020988.3(GNAO1):​c.338G>C​(p.Arg113Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R113Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	NM_020988.3	MANE Select	c.338G>C	p.Arg113Pro	missense	Exon 4 of 9	NP_066268.1
	GNAO1	NM_138736.3		c.338G>C	p.Arg113Pro	missense	Exon 4 of 8	NP_620073.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	ENST00000262493.12	TSL:1 MANE Select	c.338G>C	p.Arg113Pro	missense	Exon 4 of 9	ENSP00000262493.6
	GNAO1	ENST00000262494.13	TSL:1	c.338G>C	p.Arg113Pro	missense	Exon 4 of 8	ENSP00000262494.7
	GNAO1	ENST00000638705.1	TSL:1	c.338G>C	p.Arg113Pro	missense	Exon 4 of 8	ENSP00000491223.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.338G>C (p.R113P) alteration is located in exon 4 (coding exon 4) of the GNAO1 gene. This alteration results from a G to C substitution at nucleotide position 338, causing the arginine (R) at amino acid position 113 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.089	D
MutationAssessor	Benign	1.4	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.57
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.30	B
Vest4		0.58
MutPred		0.38		Loss of stability (P = 0.0733)
MVP		0.77
MPC		2.3
ClinPred		0.91	D
GERP RS		4.8
PromoterAI		-0.054	Neutral
Varity_R		0.62
gMVP		0.99

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: rs956210011; hg19: chr16-56362577;