Genetic Variant GNAO1:c.161+8C>T (chr16-56192624-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_020988.3(GNAO1):c.161+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,550,386 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 16 hom., cov: 26)

Exomes 𝑓: 0.00062 ( 9 hom. )

Consequence

GNAO1
NM_020988.3 splice_region, intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.668

Publications

0 publications found

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:

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

GNAO1-DT links:

GNAO1-AS1 (HGNC:24498): (GNAO1 antisense RNA 1)

GNAO1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 16-56192624-C-T is Benign according to our data. Variant chr16-56192624-C-T is described in ClinVar as Benign. ClinVar VariationId is 415873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0067 (1015/151470) while in subpopulation AFR AF = 0.0233 (959/41200). AF 95% confidence interval is 0.0221. There are 16 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 1015 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020988.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GNAO1	NM_020988.3	MANE Select	c.161+8C>T	splice_region intron	N/A	NP_066268.1	P09471-1
GNAO1	NM_138736.3		c.161+8C>T	splice_region intron	N/A	NP_620073.2	P09471-2
GNAO1-AS1	NR_026889.1		n.1902G>A	non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GNAO1	ENST00000262493.12	TSL:1 MANE Select	c.161+8C>T	splice_region intron	N/A	ENSP00000262493.6	P09471-1
GNAO1	ENST00000262494.13	TSL:1	c.161+8C>T	splice_region intron	N/A	ENSP00000262494.7	P09471-2
GNAO1	ENST00000638705.1	TSL:1	c.161+8C>T	splice_region intron	N/A	ENSP00000491223.1	P09471-1

Frequencies

GnomAD3 genomes

AF:

0.00669

AC:

1013

AN:

151354

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0233

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00177

AC:

445

AN:

251442

AF XY:

0.00124

show subpopulations

Gnomad AFR exome

AF:

0.0244

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000620

AC:

867

AN:

1398916

Hom.:

Cov.:

AF XY:

0.000572

AC XY:

400

AN XY:

699526

show subpopulations

African (AFR)

AF:

0.0223

AC:

716

AN:

32164

American (AMR)

AF:

0.00110

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25730

East Asian (EAS)

AF:

0.00

AC:

AN:

39410

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000353

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1054566

Other (OTH)

AF:

0.00136

AC:

AN:

58278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00670

AC:

1015

AN:

151470

Hom.:

Cov.:

AF XY:

0.00621

AC XY:

459

AN XY:

73970

show subpopulations

African (AFR)

AF:

0.0233

AC:

959

AN:

41200

American (AMR)

AF:

0.00263

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.000211

AC:

AN:

4746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67906

Other (OTH)

AF:

0.00522

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

143

190

238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00195

Hom.:

Bravo

AF:

0.00782

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Developmental and epileptic encephalopathy (1)

GNAO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

0.67

PromoterAI

-0.0031

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over