16-56192273-T-C

Position:

• chr16-56192273-T-C

Variant summary

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

The ENST00000262493.12(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 ENST00000262493.12 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 gene, where missense usually causes diseases (based on misZ statistic), GNAO1. . Gene score misZ 3.1919 (greater than the threshold 3.09). Trascript score misZ 4.549 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.38T>C	p.Leu13Pro	missense_variant	1/9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.38T>C	p.Leu13Pro	missense_variant	1/8		NP_620073.2
GNAO1	XR_007064866.1	n.785T>C		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.38T>C	p.Leu13Pro	missense_variant	1/9	1	NM_020988.3	ENSP00000262493	P1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2020

- -

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;.;.
MutationTaster	Benign	1.0	D;D
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;