rs143576848

chr16-56340880-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000262494.13(GNAO1):c.770A>G(p.Asn257Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,096 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 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: GNAO1 ENST00000262494.13 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.50

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.

• PP2: Missense variant where missense usually causes diseases, GNAO1
• BP4: Computational evidence support a benign effect (MetaRNN=0.039150536).
• BP6: Variant 16-56340880-A-G is Benign according to our data. Variant chr16-56340880-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 585943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000114 (166/1461760) while in subpopulation AMR AF= 0.000157 (7/44722). AF 95% confidence interval is 0.0000728. There are 1 homozygotes in gnomad4_exome. There are 83 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.723+4020A>G		intron_variant		ENST00000262493.12
GNAO1	NM_138736.3	c.770A>G	p.Asn257Ser	missense_variant	7/8
GNAO1	XM_011523003.4	c.597+4020A>G		intron_variant
GNAO1	XR_007064866.1	n.1517A>G		non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.723+4020A>G		intron_variant		1	NM_020988.3	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251456 Hom.: 1 AF XY: 0.000132 AC XY: 18 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461760 Hom.: 1 Cov.: 30 AF XY: 0.000114 AC XY: 83 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000225 Hom.: 1

Bravo AF: 0.000125

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2021

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.042
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Benign	0.20	T
Sift4G	Benign	1.0	T
Polyphen		0.62	P
Vest4		0.53
MVP		0.78
MPC		0.74
ClinPred		0.15	T
GERP RS		3.8
gMVP		0.63

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: rs143576848; hg19: chr16-56374792;