Genetic Variant GIGYF2:p.Gln1211AlafsTer54 (chr2-232847517-A-AGCAGCAGCAGCAGCAGCTGCCGCAG) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001103146.3(GIGYF2):c.3630_3631insGCAGCAGCAGCAGCAGCTGCCGCAG(p.Gln1211AlafsTer54) variant causes a frameshift change. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

GIGYF2
NM_001103146.3 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3 link	c.3630_3631insGCAGCAGCAGCAGCAGCTGCCGCAG	p.Gln1211AlafsTer54	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_3631insGCAGCAGCAGCAGCAGCTGCCGCAG	p.Gln1211AlafsTer54	frameshift_variant	Exon 27 of 29	1	NM_001103146.3	ENSP00000362664.5		Q6Y7W6-1

Frequencies

GnomAD3 genomes

AF:

0.000104

AC:

AN:

28976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00111

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000517

AC:

AN:

386956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

196740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

7242

American (AMR)

AF:

0.00

AC:

AN:

9288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4456

East Asian (EAS)

AF:

0.0000957

AC:

AN:

20902

South Asian (SAS)

AF:

0.00

AC:

AN:

48942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1536

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

268490

Other (OTH)

AF:

0.00

AC:

AN:

15792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000104

AC:

AN:

28976

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

14824

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6454

American (AMR)

AF:

0.00

AC:

AN:

2888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

474

East Asian (EAS)

AF:

0.00111

AC:

AN:

2710

South Asian (SAS)

AF:

0.00

AC:

AN:

2712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

10870

Other (OTH)

AF:

0.00

AC:

AN:

340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.4

Mutation Taster

=93/107

disease causing

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over