Genetic Variant GIGYF2:p.Gln1211AlafsTer46 (chr2-232847517-A-AG) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_001103146.3(GIGYF2):c.3630_3631insG(p.Gln1211AlafsTer46) variant causes a frameshift change. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.17 ( 237 hom., cov: 0)

Exomes 𝑓: 0.12 ( 1775 hom. )

Consequence

GIGYF2
NM_001103146.3 frameshift

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.44

Publications

3 publications found

Variant links:

Genes affected

GIGYF2 (HGNC:11960): (GRB10 interacting GYF protein 2) This gene contains CAG trinucleotide repeats and encodes a protein containing several stretches of polyglutamine residues. The encoded protein may be involved in the regulation of tyrosine kinase receptor signaling. This gene is located in a chromosomal region that was genetically linked to Parkinson disease type 11, and mutations in this gene were thought to be causative for this disease. However, more recent studies in different populations have been unable to replicate this association. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

GIGYF2 Gene-Disease associations (from GenCC):

Parkinson disease 11, autosomal dominant, susceptibility to
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

GIGYF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 2-232847517-A-AG is Benign according to our data. Variant chr2-232847517-A-AG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3 link	c.3630_3631insG	p.Gln1211AlafsTer46	frameshift_variant	Exon 27 of 29	ENST00000373563.9	NP_001096616.1	Q6Y7W6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9 link	c.3630_3631insG	p.Gln1211AlafsTer46	frameshift_variant	Exon 27 of 29	1	NM_001103146.3	ENSP00000362664.5		Q6Y7W6-1

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

5019

AN:

28964

Hom.:

237

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0445

Gnomad AMI

AF:

0.236

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.114

Gnomad EAS

AF:

0.439

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.367

Gnomad MID

AF:

0.185

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.185

GnomAD2 exomes

AF:

0.0339

AC:

7827

AN:

230696

AF XY:

0.0342

show subpopulations

Gnomad AFR exome

AF:

0.00395

Gnomad AMR exome

AF:

0.0487

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.129

Gnomad FIN exome

AF:

0.0452

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.0250

GnomAD4 exome

AF:

0.120

AC:

46437

AN:

386888

Hom.:

1775

Cov.:

AF XY:

0.122

AC XY:

23962

AN XY:

196702

show subpopulations

African (AFR)

AF:

0.0313

AC:

227

AN:

7242

American (AMR)

AF:

0.333

AC:

3088

AN:

9282

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

468

AN:

4454

East Asian (EAS)

AF:

0.458

AC:

9565

AN:

20892

South Asian (SAS)

AF:

0.137

AC:

6720

AN:

48930

European-Finnish (FIN)

AF:

0.352

AC:

3620

AN:

10296

Middle Eastern (MID)

AF:

0.138

AC:

212

AN:

1536

European-Non Finnish (NFE)

AF:

0.0763

AC:

20474

AN:

268468

Other (OTH)

AF:

0.131

AC:

2063

AN:

15788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2216

4432

6648

8864

11080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

956

1912

2868

3824

4780

<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:

0.173

AC:

5019

AN:

28976

Hom.:

237

Cov.:

AF XY:

0.188

AC XY:

2792

AN XY:

14836

show subpopulations

African (AFR)

AF:

0.0448

AC:

289

AN:

6456

American (AMR)

AF:

0.259

AC:

751

AN:

2898

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

AN:

474

East Asian (EAS)

AF:

0.439

AC:

1183

AN:

2696

South Asian (SAS)

AF:

0.154

AC:

416

AN:

2706

European-Finnish (FIN)

AF:

0.367

AC:

813

AN:

2218

Middle Eastern (MID)

AF:

0.182

AC:

AN:

European-Non Finnish (NFE)

AF:

0.127

AC:

1385

AN:

10866

Other (OTH)

AF:

0.170

AC:

AN:

358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

228

456

684

912

1140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 39.59% east asian with 179 homozygotes in ExAC (VQSRTrancheINDEL96.00to97.00) -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.4

Mutation Taster

=200/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over