rs1799917

Variant names:

• chr16-56343836-A-C
• rs1799917
• ENST00000262494.13:c.951A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-56343836-A-C
• chr16-56343836-A-G
• chr16-56343836-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000262494.13(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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 ENST00000262494.13 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 28 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 1963 AN: 111088 Hom.: 0 Cov.: 28

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: 0 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: 0 AN: 1460158 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726380

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110950

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome AF: 0.0176 AC: 1962 AN: 111198 Hom.: 0 Cov.: 28 AF XY: 0.0165 AC XY: 896 AN XY: 54288

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0218 AC: 717 AN: 32958

American (AMR) AF: 0.0181 AC: 181 AN: 9992

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 44 AN: 2300

East Asian (EAS) AF: 0.0221 AC: 71 AN: 3208

South Asian (SAS) AF: 0.0137 AC: 53 AN: 3858

European-Finnish (FIN) AF: 0.00536 AC: 42 AN: 7834

Middle Eastern (MID) AF: 0.0105 AC: 2 AN: 190

European-Non Finnish (NFE) AF: 0.0168 AC: 819 AN: 48726

Other (OTH) AF: 0.0204 AC: 30 AN: 1474

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000121 Hom.: 16571

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Pathogenic	0.98	D
PhyloP100		2.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Vest4		0.76
ClinPred		0.99	D
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

Other links and lift over

dbSNP: rs1799917; hg19: chr16-56377748;