rs141057479

Variant names:

• chr16-56328741-A-C
• NM_020988.3:c.414A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-56328741-A-C
• chr16-56328741-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_020988.3(GNAO1):​c.414A>C​(p.Gln138His) variant causes a missense change involving the alteration of a non-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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GNAO1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 70 curated pathogenic missense variants (we use a threshold of 10). The gene has 43 curated benign missense variants. Gene score misZ: 3.1919 (above the threshold of 3.09). Trascript score misZ: 4.549 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 17, neurodevelopmental disorder with involuntary movements, developmental and epileptic encephalopathy, movement disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.414A>C	p.Gln138His	missense_variant	Exon 4 of 9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.414A>C	p.Gln138His	missense_variant	Exon 4 of 8		NP_620073.2
GNAO1	XM_011523003.4	c.288A>C	p.Gln96His	missense_variant	Exon 4 of 9		XP_011521305.1
GNAO1	XR_007064866.1	n.1161A>C		non_coding_transcript_exon_variant	Exon 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.414A>C	p.Gln138His	missense_variant	Exon 4 of 9	1	NM_020988.3	ENSP00000262493.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	2.9	M;M;M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D;.;D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.0060	D;.;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.78
MutPred		0.75		Gain of catalytic residue at Q138 (P = 0.0801);Gain of catalytic residue at Q138 (P = 0.0801);Gain of catalytic residue at Q138 (P = 0.0801);.;
MVP		0.92
MPC		1.4
ClinPred		0.99	D
GERP RS		1.7
Varity_R		0.91
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-56362653;