2-232756197-CTTTTTTTTTTTTTT-CTTTTTTTTTTT

Variant names:

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

Variant summary

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

The NM_001103146.3(GIGYF2):​c.268-8_268-6delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 696,916 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 0)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: GIGYF2 NM_001103146.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• 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_268-6delTTT		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.268-25_268-23delTTT		intron_variant	Intron 5 of 28	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes AF: 0.0000292 AC: 3 AN: 102702 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0103 AC: 6113 AN: 594248 Hom.: 0 AF XY: 0.00985 AC XY: 3105 AN XY: 315254

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

African (AFR) AF: 0.0184 AC: 266 AN: 14462

American (AMR) AF: 0.0104 AC: 261 AN: 25188

Ashkenazi Jewish (ASJ) AF: 0.00990 AC: 155 AN: 15652

East Asian (EAS) AF: 0.0143 AC: 433 AN: 30324

South Asian (SAS) AF: 0.00787 AC: 375 AN: 47640

European-Finnish (FIN) AF: 0.00876 AC: 316 AN: 36056

Middle Eastern (MID) AF: 0.00995 AC: 22 AN: 2210

European-Non Finnish (NFE) AF: 0.0100 AC: 3943 AN: 393744

Other (OTH) AF: 0.0118 AC: 342 AN: 28972

⚠️ 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: 0.0000292 AC: 3 AN: 102668 Hom.: 0 Cov.: 0 AF XY: 0.0000420 AC XY: 2 AN XY: 47566

African (AFR) AF: 0.000115 AC: 3 AN: 26036

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2792

East Asian (EAS) AF: 0.00 AC: 0 AN: 3744

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: 0.00 AC: 0 AN: 52568

Other (OTH) AF: 0.00 AC: 0 AN: 1330

Alfa AF: 0.00 Hom.: 144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs759525243; hg19: chr2-233620907;