ENST00000262494.13:c.951A>C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BS1 BS2

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. 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

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 -7 ACMG points.

• PP2: Missense variant in the GNAO1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 70 curated pathogenic missense variants (we use a threshold of 10). The gene has 43 curated benign missense variants. Gene score misZ: 3.1919 (above the threshold of 3.09). Trascript score misZ: 3.4487 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 17, neurodevelopmental disorder with involuntary movements, developmental and epileptic encephalopathy, movement disorder.
• 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 male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• 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	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	XM_011523003.4	c.597+6976A>C		intron_variant	Intron 6 of 8		XP_011521305.1
GNAO1	XR_007064866.1	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	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

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.0181

Gnomad4 ASJ AF: 0.0191

Gnomad4 EAS AF: 0.0221

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00536

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.000140 Hom.: 14274

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.61		Loss of methylation at K317 (P = 0.0011);
MVP		0.71
MPC		1.1
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

Publications

LitVar

Other links and lift over

dbSNP: rs1799917; hg19: chr16-56377748;