2-232847517-A-AGCAGCAG

Variant names:

• chr2-232847517-A-AGCAGCAG
• rs775324034
• NM_001103146.3:c.3630_3631insGCAGCAG

Variant summary

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

The NM_001103146.3(GIGYF2):​c.3630_3631insGCAGCAG​(p.Gln1211AlafsTer48) variant causes a frameshift change. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: GIGYF2 NM_001103146.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.44
• Publications: 0 publications found

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

ACMG classification

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	c.3630_3631insGCAGCAG	p.Gln1211AlafsTer48	frameshift_variant	Exon 27 of 29	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.3630_3631insGCAGCAG	p.Gln1211AlafsTer48	frameshift_variant	Exon 27 of 29	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000517 AC: 2 AN: 386956 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 196740

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7242

American (AMR) AF: 0.00 AC: 0 AN: 9288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4456

East Asian (EAS) AF: 0.00 AC: 0 AN: 20902

South Asian (SAS) AF: 0.0000204 AC: 1 AN: 48942

European-Finnish (FIN) AF: 0.0000970 AC: 1 AN: 10308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1536

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 268490

Other (OTH) AF: 0.00 AC: 0 AN: 15792

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4

Splicing

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

Other links and lift over

dbSNP: rs775324034; hg19: chr2-233712227;