dbSNP rs1799917: GNAO1:p.Lys317Asn (chr16-56343836-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_138736.3(GNAO1):c.951A>C(p.Lys317Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 111,198 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K317R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.018 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAO1
NM_138736.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.93

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0176 (1962/111198) while in subpopulation EAS AF = 0.0221 (71/3208). AF 95% confidence interval is 0.0204. There are 0 homozygotes in GnomAd4. There are 896 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 1962 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3 link	c.723+6976A>C		intron_variant	Intron 6 of 8	ENST00000262493.12	NP_066268.1	P09471-1Q8N6I9B3KP89
GNAO1	NM_138736.3 link	c.951A>C	p.Lys317Asn	missense_variant	Exon 8 of 8		NP_620073.2	P09471-2Q8N6I9B3KP89Q6AWC5
GNAO1	XM_011523003.4 link	c.597+6976A>C		intron_variant	Intron 6 of 8		XP_011521305.1
GNAO1	XR_007064866.1 link	n.1698A>C		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12 link	c.723+6976A>C		intron_variant	Intron 6 of 8	1	NM_020988.3	ENSP00000262493.6		P09471-1

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

1963

AN:

111088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.00456

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.0191

Gnomad EAS

AF:

0.0220

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.00536

Gnomad MID

AF:

0.00990

Gnomad NFE

AF:

0.0168

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.00

AC:

AN:

250710

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726380

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33406

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44630

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26088

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39604

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86070

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53320

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1110950

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60326

GnomAD4 genome

AF:

0.0176

AC:

1962

AN:

111198

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

896

AN XY:

54288

show subpopulations

Gnomad4 AFR

AF:

0.0218

AC:

0.021755

AN:

0.021755

Gnomad4 AMR

AF:

0.0181

AC:

0.0181145

AN:

0.0181145

Gnomad4 ASJ

AF:

0.0191

AC:

0.0191304

AN:

0.0191304

Gnomad4 EAS

AF:

0.0221

AC:

0.0221322

AN:

0.0221322

Gnomad4 SAS

AF:

0.0137

AC:

0.0137377

AN:

0.0137377

Gnomad4 FIN

AF:

0.00536

AC:

0.00536125

AN:

0.00536125

Gnomad4 NFE

AF:

0.0168

AC:

0.0168083

AN:

0.0168083

Gnomad4 OTH

AF:

0.0204

AC:

0.0203528

AN:

0.0203528

⚠️ The allele balance in gnomAD4 Genomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

215

430

644

859

1074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000121

Hom.:

16571

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.79

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.67

MetaRNN

Uncertain

0.50

MetaSVM

Pathogenic

0.98

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.76

MutPred

0.61

Loss of methylation at K317 (P = 0.0011);

MVP

0.71

MPC

1.1

ClinPred

0.99

GERP RS

4.4

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over