2-232847517-A-AGCAG

Variant names:

• chr2-232847517-A-AGCAG
• rs775324034
• NM_001103146.3:c.3630_3631insGCAG

Variant summary

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

The NM_001103146.3(GIGYF2):​c.3630_3631insGCAG​(p.Gln1211AlafsTer47) 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: 0.0000078 (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: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103146.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	NM_001103146.3	MANE Select	c.3630_3631insGCAG	p.Gln1211AlafsTer47	frameshift	Exon 27 of 29	NP_001096616.1	Q6Y7W6-1
	GIGYF2	NM_001103147.2		c.3693_3694insGCAG	p.Gln1232AlafsTer47	frameshift	Exon 29 of 31	NP_001096617.1	Q6Y7W6-3
	GIGYF2	NM_015575.4		c.3630_3631insGCAG	p.Gln1211AlafsTer47	frameshift	Exon 29 of 31	NP_056390.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.3630_3631insGCAG	p.Gln1211AlafsTer47	frameshift	Exon 27 of 29	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.3693_3694insGCAG	p.Gln1232AlafsTer47	frameshift	Exon 29 of 31	ENSP00000387170.3	Q6Y7W6-3
	GIGYF2	ENST00000409547.5	TSL:1	c.3630_3631insGCAG	p.Gln1211AlafsTer47	frameshift	Exon 29 of 31	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000775 AC: 3 AN: 386956 Hom.: 0 Cov.: 0 AF XY: 0.0000152 AC XY: 3 AN XY: 196740

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: 0.0000613 AC: 3 AN: 48942

European-Finnish (FIN) AF: 0.00 AC: 0 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

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;