Genetic Variant ENST00000665141.2:n.47+439C>T (chr16-56191124-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000665141.2(GNAO1-DT):n.47+439C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.082 in 149,136 control chromosomes in the GnomAD database, including 553 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.082 ( 553 hom., cov: 31)

Exomes 𝑓: 0.071 ( 0 hom. )

Consequence

GNAO1-DT
ENST00000665141.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0580

Publications

2 publications found

Variant links:

Genes affected

GNAO1-DT (HGNC:27543): (GNAO1 divergent transcript)

GNAO1-DT links:

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)

GNAO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1-DT	NR_027078.2 link	n.-30C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank
GNAO1-DT	ENST00000665141.2 link	n.47+439C>T	intron_variant	Intron 1 of 3
GNAO1	ENST00000714052.1 link	n.102-1134G>A	intron_variant	Intron 1 of 2
GNAO1-DT	ENST00000715694.1 link	n.1976+1419C>T	intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0820

AC:

12219

AN:

149002

Hom.:

552

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.0989

Gnomad AMR

AF:

0.0503

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.0342

Gnomad SAS

AF:

0.0937

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.0321

Gnomad NFE

AF:

0.0754

Gnomad OTH

AF:

0.0586

GnomAD4 exome

AF:

0.0714

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0455

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0909

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0820

AC:

12231

AN:

149108

Hom.:

553

Cov.:

AF XY:

0.0825

AC XY:

6006

AN XY:

72782

show subpopulations

African (AFR)

AF:

0.106

AC:

4373

AN:

41148

American (AMR)

AF:

0.0506

AC:

760

AN:

15032

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

158

AN:

3428

East Asian (EAS)

AF:

0.0342

AC:

171

AN:

5006

South Asian (SAS)

AF:

0.0940

AC:

452

AN:

4806

European-Finnish (FIN)

AF:

0.110

AC:

1063

AN:

9652

Middle Eastern (MID)

AF:

0.0276

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0754

AC:

5036

AN:

66766

Other (OTH)

AF:

0.0580

AC:

120

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

509

1018

1526

2035

2544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0792

Hom.:

Bravo

AF:

0.0755

Asia WGS

AF:

0.0730

AC:

247

AN:

3378

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 31, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

-0.058

PromoterAI

-0.067

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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ENST00000665141.2:n.47+439C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over