rs116862304

chr16-56354981-C-T

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.993C>T(p.Asn331=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,613,244 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 31)
  • Exomes 𝑓: 0.017 (258 hom.)
• Consequence: GNAO1 NM_020988.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.46

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=-0.46).
• BP6: Variant 16-56354981-C-T is Benign according to our data. Variant chr16-56354981-C-T is described in ClinVar as [Benign]. Clinvar id is 241368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1688/152292) while in subpopulation NFE AF= 0.0194 (1317/68036). AF 95% confidence interval is 0.0185. There are 12 homozygotes in gnomad4. There are 747 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1689 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.993C>T	p.Asn331=	synonymous_variant	8/9	ENST00000262493.12
GNAO1	XM_011523003.4	c.867C>T	p.Asn289=	synonymous_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.993C>T	p.Asn331=	synonymous_variant	8/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1689 AN: 152174 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.0108 AC: 2728 AN: 251456 Hom.: 22 AF XY: 0.0106 AC XY: 1439 AN XY: 135904

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0172 AC: 25178 AN: 1460952 Hom.: 258 Cov.: 30 AF XY: 0.0166 AC XY: 12082 AN XY: 726788

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00425

Gnomad4 ASJ exome AF: 0.00670

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00290

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0111 AC: 1688 AN: 152292 Hom.: 12 Cov.: 31 AF XY: 0.0100 AC XY: 747 AN XY: 74458

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00943

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.0160 Hom.: 15

Bravo AF: 0.0109

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0168

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2016

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	4.1
Dann	Benign	0.85

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: rs116862304; hg19: chr16-56388893;