rs116277860

Variant names:

• chr16-56340959-G-A
• rs116277860
• ENST00000262494.13:c.849G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-56340959-G-A
• chr16-56340959-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_138736.3(GNAO1):​c.849G>A​(p.Pro283Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,890 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (28 hom.)
• Consequence: GNAO1 NM_138736.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.443
• Publications: 2 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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• movement disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• neurodevelopmental disorder with involuntary movements

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 16-56340959-G-A is Benign according to our data. Variant chr16-56340959-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.443 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00912 (1388/152270) while in subpopulation AFR AF = 0.0321 (1333/41552). AF 95% confidence interval is 0.0306. There are 21 homozygotes in GnomAd4. There are 644 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1388 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138736.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	NM_020988.3	MANE Select	c.723+4099G>A		intron	N/A	NP_066268.1
	GNAO1	NM_138736.3		c.849G>A	p.Pro283Pro	synonymous	Exon 7 of 8	NP_620073.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	ENST00000262494.13	TSL:1	c.849G>A	p.Pro283Pro	synonymous	Exon 7 of 8	ENSP00000262494.7
	GNAO1	ENST00000262493.12	TSL:1 MANE Select	c.723+4099G>A		intron	N/A	ENSP00000262493.6
	GNAO1	ENST00000638705.1	TSL:1	c.723+4099G>A		intron	N/A	ENSP00000491223.1

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1387 AN: 152152 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00243 AC: 612 AN: 251386 AF XY: 0.00176

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000976 AC: 1426 AN: 1461620 Hom.: 28 Cov.: 30 AF XY: 0.000822 AC XY: 598 AN XY: 727118

African (AFR) AF: 0.0347 AC: 1160 AN: 33468

American (AMR) AF: 0.00134 AC: 60 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111852

Other (OTH) AF: 0.00215 AC: 130 AN: 60384

GnomAD4 genome AF: 0.00912 AC: 1388 AN: 152270 Hom.: 21 Cov.: 33 AF XY: 0.00865 AC XY: 644 AN XY: 74458

African (AFR) AF: 0.0321 AC: 1333 AN: 41552

American (AMR) AF: 0.00281 AC: 43 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00411 Hom.: 7

Bravo AF: 0.0101

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	GNAO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.61
PhyloP100		-0.44
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs116277860; hg19: chr16-56374871; COSMIC: COSV99341935;