16-56192351-T-C

Variant names:

• chr16-56192351-T-C
• rs1555499769
• NM_020988.3:c.116T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_020988.3(GNAO1):​c.116T>C​(p.Leu39Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L39F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAO1 NM_020988.3 missense, splice_region
• Scores: Splicing: ADA: 0.2892
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.70
• 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-DT (HGNC:27543): (GNAO1 divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_020988.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 16-56192351-T-C is Pathogenic according to our data. Variant chr16-56192351-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521814.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.116T>C	p.Leu39Pro	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.116T>C	p.Leu39Pro	missense_variant, splice_region_variant	Exon 1 of 8		NP_620073.2
GNAO1	XR_007064866.1	n.863T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 9
GNAO1	XM_011523003.4	c.-603T>C		upstream_gene_variant			XP_011521305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.116T>C	p.Leu39Pro	missense_variant, splice_region_variant	Exon 1 of 9	1	NM_020988.3	ENSP00000262493.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

May 19, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D;T;T;D;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;H;H;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.8	D;.;.;D;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Uncertain	0.035	D;.;.;D;D;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.92
MutPred		0.92		Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);
MVP		0.99
MPC		3.5
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.033	Neutral
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.29
dbscSNV1_RF	Benign	0.60
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: rs1555499769; hg19: chr16-56226263;