16-56192273-T-C

Variant names:

• chr16-56192273-T-C
• rs1555499768
• NM_020988.3:c.38T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_020988.3(GNAO1):​c.38T>C​(p.Leu13Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.83

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.
• PP5: Variant 16-56192273-T-C is Pathogenic according to our data. Variant chr16-56192273-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 493183.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.38T>C	p.Leu13Pro	missense_variant	Exon 1 of 9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.38T>C	p.Leu13Pro	missense_variant	Exon 1 of 8		NP_620073.2
GNAO1	XR_007064866.1	n.785T>C		non_coding_transcript_exon_variant	Exon 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.38T>C	p.Leu13Pro	missense_variant	Exon 1 of 9	1	NM_020988.3	ENSP00000262493.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;.;T;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.1	L;.;L;L;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.3	N;.;.;N;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.16	T;.;.;T;.;.
Sift4G	Benign	0.24	T;.;.;T;T;.
Polyphen		0.0070	B;.;B;B;.;.
Vest4		0.34
MutPred		0.48		Gain of glycosylation at L13 (P = 0.0162);Gain of glycosylation at L13 (P = 0.0162);Gain of glycosylation at L13 (P = 0.0162);Gain of glycosylation at L13 (P = 0.0162);Gain of glycosylation at L13 (P = 0.0162);Gain of glycosylation at L13 (P = 0.0162);
MVP		0.87
MPC		2.1
ClinPred		0.81	D
GERP RS		3.6
Varity_R		0.95
gMVP		1.0

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: rs1555499768; hg19: chr16-56226185;