2-232756197-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTT

Variant names:

• chr2-232756197-C-CTTT
• rs759525243
• NM_001103146.3:c.268-8_268-6dupTTT

Variant summary

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

The NM_001103146.3(GIGYF2):​c.268-8_268-6dupTTT 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 0.0041 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0081 (9 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: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.268-8_268-6dupTTT		splice_region_variant, intron_variant	Intron 5 of 28	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.268-26_268-25insTTT		intron_variant	Intron 5 of 28	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 416 AN: 102680 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00219

Gnomad AMI AF: 0.00683

Gnomad AMR AF: 0.00252

Gnomad ASJ AF: 0.00608

Gnomad EAS AF: 0.000797

Gnomad SAS AF: 0.00342

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00571

Gnomad OTH AF: 0.00152

GnomAD4 exome AF: 0.00806 AC: 4861 AN: 603084 Hom.: 9 Cov.: 0 AF XY: 0.00851 AC XY: 2721 AN XY: 319664

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

African (AFR) AF: 0.00499 AC: 74 AN: 14820

American (AMR) AF: 0.00894 AC: 229 AN: 25622

Ashkenazi Jewish (ASJ) AF: 0.00829 AC: 132 AN: 15932

East Asian (EAS) AF: 0.00367 AC: 115 AN: 31336

South Asian (SAS) AF: 0.0214 AC: 1015 AN: 47466

European-Finnish (FIN) AF: 0.00505 AC: 186 AN: 36824

Middle Eastern (MID) AF: 0.00754 AC: 17 AN: 2254

European-Non Finnish (NFE) AF: 0.00724 AC: 2891 AN: 399346

Other (OTH) AF: 0.00685 AC: 202 AN: 29484

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00405 AC: 416 AN: 102646 Hom.: 0 Cov.: 0 AF XY: 0.00385 AC XY: 183 AN XY: 47552

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

African (AFR) AF: 0.00219 AC: 57 AN: 26036

American (AMR) AF: 0.00252 AC: 22 AN: 8738

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 17 AN: 2794

East Asian (EAS) AF: 0.000801 AC: 3 AN: 3746

South Asian (SAS) AF: 0.00345 AC: 10 AN: 2898

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 150

European-Non Finnish (NFE) AF: 0.00571 AC: 300 AN: 52546

Other (OTH) AF: 0.00150 AC: 2 AN: 1330

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism

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;