Genetic Variant GNAO1:p.Lys317Lys (chr16-56343836-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_138736.3(GNAO1):c.951A>G(p.Lys317Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,580,160 control chromosomes in the GnomAD database, including 108,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 9136 hom., cov: 28)

Exomes 𝑓: 0.36 ( 99337 hom. )

Consequence

GNAO1
NM_138736.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 16-56343836-A-G is Benign according to our data. Variant chr16-56343836-A-G is described in ClinVar as [Benign]. Clinvar id is 585945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.93 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3 link	c.723+6976A>G		intron_variant	Intron 6 of 8	ENST00000262493.12	NP_066268.1	P09471-1Q8N6I9B3KP89
GNAO1	NM_138736.3 link	c.951A>G	p.Lys317Lys	synonymous_variant	Exon 8 of 8		NP_620073.2	P09471-2Q8N6I9B3KP89Q6AWC5
GNAO1	XM_011523003.4 link	c.597+6976A>G		intron_variant	Intron 6 of 8		XP_011521305.1
GNAO1	XR_007064866.1 link	n.1698A>G		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>G		intron_variant	Intron 6 of 8	1	NM_020988.3	ENSP00000262493.6		P09471-1

Frequencies

GnomAD3 genomes

AF:

0.465

AC:

55766

AN:

119914

Hom.:

9114

Cov.:

show subpopulations

Gnomad AFR

AF:

0.587

Gnomad AMI

AF:

0.483

Gnomad AMR

AF:

0.367

Gnomad ASJ

AF:

0.383

Gnomad EAS

AF:

0.309

Gnomad SAS

AF:

0.507

Gnomad FIN

AF:

0.332

Gnomad MID

AF:

0.406

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.416

GnomAD3 exomes

AF:

0.345

AC:

86379

AN:

250710

Hom.:

16095

AF XY:

0.348

AC XY:

47128

AN XY:

135568

show subpopulations

Gnomad AFR exome

AF:

0.579

Gnomad AMR exome

AF:

0.248

Gnomad ASJ exome

AF:

0.295

Gnomad EAS exome

AF:

0.197

Gnomad SAS exome

AF:

0.463

Gnomad FIN exome

AF:

0.274

Gnomad NFE exome

AF:

0.351

Gnomad OTH exome

AF:

0.335

GnomAD4 exome

AF:

0.363

AC:

530211

AN:

1460142

Hom.:

99337

Cov.:

AF XY:

0.364

AC XY:

264269

AN XY:

726440

show subpopulations

Gnomad4 AFR exome

AF:

0.581

Gnomad4 AMR exome

AF:

0.250

Gnomad4 ASJ exome

AF:

0.291

Gnomad4 EAS exome

AF:

0.210

Gnomad4 SAS exome

AF:

0.454

Gnomad4 FIN exome

AF:

0.271

Gnomad4 NFE exome

AF:

0.366

Gnomad4 OTH exome

AF:

0.362

GnomAD4 genome

AF:

0.465

AC:

55826

AN:

120018

Hom.:

9136

Cov.:

AF XY:

0.461

AC XY:

26876

AN XY:

58342

show subpopulations

Gnomad4 AFR

AF:

0.587

Gnomad4 AMR

AF:

0.367

Gnomad4 ASJ

AF:

0.383

Gnomad4 EAS

AF:

0.308

Gnomad4 SAS

AF:

0.508

Gnomad4 FIN

AF:

0.332

Gnomad4 NFE

AF:

0.434

Gnomad4 OTH

AF:

0.416

Alfa

AF:

0.362

Hom.:

14274

Bravo

AF:

0.406

EpiCase

AF:

0.346

EpiControl

AF:

0.342

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.64

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over