rs1555507479

Positions:

• chr16-56336799-C-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The ENST00000262493.12(GNAO1):​c.662C>A​(p.Ala221Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: GNAO1 ENST00000262493.12 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.16

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000262493.12
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 16-56336799-C-A is Pathogenic according to our data. Variant chr16-56336799-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.662C>A	p.Ala221Asp	missense_variant	6/9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.662C>A	p.Ala221Asp	missense_variant	6/8		NP_620073.2
GNAO1	XM_011523003.4	c.536C>A	p.Ala179Asp	missense_variant	6/9		XP_011521305.1
GNAO1	XR_007064866.1	n.1409C>A		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.662C>A	p.Ala221Asp	missense_variant	6/9	1	NM_020988.3	ENSP00000262493	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with involuntary movements Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 15, 2018	The heterozygous p.Ala221Asp variant was identified by our study, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the UDN, in one individual with neurodevelopmental disorder with involuntary movements. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to definitively determine pathogenicity. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Dec 01, 2016	This variant, which is de novo in our patient, is novel (absent from 1000 Genomes, ExAC, gnomAD & Geno2MP databases), and is predicted to be damaging (SIFT, PolyPhen2, MutationTaster), and the patient's clinical presentation is similar to other reported cases. This individual has been reported in PMID: 30682224 (patient 8). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.3	D;.;D;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Pathogenic	0.0010	D;.;D;.;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.93
MutPred		0.82		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;.;
MVP		0.96
MPC		3.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
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: rs1555507479; hg19: chr16-56370711; COSMIC: COSV52614248; COSMIC: COSV52614248;