2-232756197-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTT

Variant names:

• chr2-232756197-C-CTTTTTT
• rs759525243
• NM_001103146.3:c.268-11_268-6dupTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001103146.3(GIGYF2):​c.268-11_268-6dupTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000088 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: GIGYF2 NM_001103146.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.876
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.268-11_268-6dupTTTTTT		splice_region intron	N/A	NP_001096616.1	Q6Y7W6-1
	GIGYF2	NM_001103147.2		c.268-11_268-6dupTTTTTT		splice_region intron	N/A	NP_001096617.1	Q6Y7W6-3
	GIGYF2	NM_015575.4		c.268-11_268-6dupTTTTTT		splice_region intron	N/A	NP_056390.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.268-26_268-25insTTTTTT		intron	N/A	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.268-26_268-25insTTTTTT		intron	N/A	ENSP00000387170.3	Q6Y7W6-3
	GIGYF2	ENST00000409547.5	TSL:1	c.268-26_268-25insTTTTTT		intron	N/A	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes AF: 0.0000876 AC: 9 AN: 102710 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000358

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000114

Gnomad OTH AF: 0.000759

GnomAD4 exome AF: 0.000250 AC: 152 AN: 607800 Hom.: 1 Cov.: 0 AF XY: 0.000267 AC XY: 86 AN XY: 322302

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

African (AFR) AF: 0.000135 AC: 2 AN: 14866

American (AMR) AF: 0.000505 AC: 13 AN: 25766

Ashkenazi Jewish (ASJ) AF: 0.000187 AC: 3 AN: 16078

East Asian (EAS) AF: 0.000255 AC: 8 AN: 31426

South Asian (SAS) AF: 0.000746 AC: 36 AN: 48280

European-Finnish (FIN) AF: 0.000189 AC: 7 AN: 37006

Middle Eastern (MID) AF: 0.000441 AC: 1 AN: 2268

European-Non Finnish (NFE) AF: 0.000194 AC: 78 AN: 402376

Other (OTH) AF: 0.000135 AC: 4 AN: 29734

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000877 AC: 9 AN: 102676 Hom.: 0 Cov.: 0 AF XY: 0.0000841 AC XY: 4 AN XY: 47570

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

African (AFR) AF: 0.0000384 AC: 1 AN: 26038

American (AMR) AF: 0.00 AC: 0 AN: 8742

Ashkenazi Jewish (ASJ) AF: 0.000358 AC: 1 AN: 2792

East Asian (EAS) AF: 0.00 AC: 0 AN: 3746

South Asian (SAS) AF: 0.00 AC: 0 AN: 2896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 152

European-Non Finnish (NFE) AF: 0.000114 AC: 6 AN: 52572

Other (OTH) AF: 0.000752 AC: 1 AN: 1330

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00618283), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88

Splicing

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

Other links and lift over

dbSNP: rs759525243; hg19: chr2-233620907;