16-56328752-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Moderate BP6_Moderate BS1 BS2

The NM_020988.3(GNAO1):c.425A>G(p.Asn142Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N142T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.28

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 -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GNAO1
• BP4: Computational evidence support a benign effect (MetaRNN=0.18293759).
• BP6: Variant 16-56328752-A-G is Benign according to our data. Variant chr16-56328752-A-G is described in ClinVar as [Benign]. Clinvar id is 461356.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000657 (10/152184) while in subpopulation AMR AF= 0.000262 (4/15286). AF 95% confidence interval is 0.0000888. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.425A>G	p.Asn142Ser	missense_variant	4/9	ENST00000262493.12
GNAO1	NM_138736.3	c.425A>G	p.Asn142Ser	missense_variant	4/8
GNAO1	XM_011523003.4	c.299A>G	p.Asn100Ser	missense_variant	4/9
GNAO1	XR_007064866.1	n.1172A>G		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.425A>G	p.Asn142Ser	missense_variant	4/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251476 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

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: 0.0000287 AC: 42 AN: 1461576 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727102

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74346

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	18
Dann	Benign	0.53
DEOGEN2	Benign	0.31	T;T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	-0.65	N;N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.15	N;.;N;.
REVEL	Uncertain	0.32
Sift	Benign	1.0	T;.;T;.
Sift4G	Benign	0.66	T;.;T;.
Polyphen		0.0	B;B;B;.
Vest4		0.19
MutPred		0.29		Gain of phosphorylation at N142 (P = 0.0458);Gain of phosphorylation at N142 (P = 0.0458);Gain of phosphorylation at N142 (P = 0.0458);.;
MVP		0.41
MPC		1.2
ClinPred		0.069	T
GERP RS		5.0
Varity_R		0.16
gMVP		0.61

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: rs758424351; hg19: chr16-56362664; COSMIC: COSV52614953;