16-56334738-C-G

Variant names:

• chr16-56334738-C-G
• rs144771965
• NM_020988.3:c.474C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_020988.3(GNAO1):​c.474C>G​(p.Asp158Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. D158D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.09
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_020988.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.474C>G	p.Asp158Glu	missense_variant	Exon 5 of 9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.474C>G	p.Asp158Glu	missense_variant	Exon 5 of 8		NP_620073.2
GNAO1	XM_011523003.4	c.348C>G	p.Asp116Glu	missense_variant	Exon 5 of 9		XP_011521305.1
GNAO1	XR_007064866.1	n.1221C>G		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.474C>G	p.Asp158Glu	missense_variant	Exon 5 of 9	1	NM_020988.3	ENSP00000262493.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 17 Uncertain:1

Nov 02, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;.;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.4	L;L;L;.
PhyloP100		4.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N;.;N;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.018	D;.;D;D
Sift4G	Benign	0.24	T;.;T;.
Polyphen		0.96	D;D;D;.
Vest4		0.55
MutPred		0.60		Gain of ubiquitination at K154 (P = 0.1103);Gain of ubiquitination at K154 (P = 0.1103);Gain of ubiquitination at K154 (P = 0.1103);.;
MVP		0.73
MPC		2.4
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.51
gMVP		0.90

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: rs144771965; hg19: chr16-56368650;