rs139334934

chr16-56192262-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020988.3(GNAO1):c.27G>A(p.Glu9=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,605,732 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00057 (1 hom.)
• Consequence: GNAO1 NM_020988.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.65

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-56192262-G-A is Benign according to our data. Variant chr16-56192262-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 461353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000309 (47/152196) while in subpopulation NFE AF= 0.000485 (33/68024). AF 95% confidence interval is 0.000355. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.27G>A	p.Glu9=	synonymous_variant	1/9	ENST00000262493.12
GNAO1	NM_138736.3	c.27G>A	p.Glu9=	synonymous_variant	1/8
GNAO1	XR_007064866.1	n.774G>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.27G>A	p.Glu9=	synonymous_variant	1/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000366 AC: 88 AN: 240158 Hom.: 0 AF XY: 0.000322 AC XY: 42 AN XY: 130582

Gnomad AFR exome AF: 0.0000666

Gnomad AMR exome AF: 0.000530

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000572 AC: 832 AN: 1453536 Hom.: 1 Cov.: 29 AF XY: 0.000537 AC XY: 388 AN XY: 722876

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000563

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000154

Gnomad4 NFE exome AF: 0.000692

Gnomad4 OTH exome AF: 0.000432

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152196 Hom.: 0 Cov.: 31 AF XY: 0.000296 AC XY: 22 AN XY: 74342

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000261

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	GNAO1: BP4, BP7 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

GNAO1-Related Condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	14
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139334934; hg19: chr16-56226174;