2-232756197-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTT

Variant names:

• chr2-232756197-C-CT
• rs759525243
• NM_001103146.3:c.268-6dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001103146.3(GIGYF2):​c.268-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.37 (7850 hom., cov: 0)
  • Exomes 𝑓: 0.20 (356 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.268-6dupT		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_268-25insT		intron_variant	Intron 5 of 28	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes AF: 0.370 AC: 38026 AN: 102874 Hom.: 7851 Cov.: 0

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.359

GnomAD4 exome AF: 0.196 AC: 116562 AN: 594856 Hom.: 356 Cov.: 0 AF XY: 0.197 AC XY: 62135 AN XY: 315158

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

African (AFR) AF: 0.140 AC: 2023 AN: 14500

American (AMR) AF: 0.127 AC: 3229 AN: 25334

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 3255 AN: 15754

East Asian (EAS) AF: 0.103 AC: 3154 AN: 30626

South Asian (SAS) AF: 0.196 AC: 9244 AN: 47270

European-Finnish (FIN) AF: 0.141 AC: 5129 AN: 36282

Middle Eastern (MID) AF: 0.214 AC: 474 AN: 2216

European-Non Finnish (NFE) AF: 0.213 AC: 84011 AN: 393858

Other (OTH) AF: 0.208 AC: 6043 AN: 29016

⚠️ 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: 0.370 AC: 38001 AN: 102840 Hom.: 7850 Cov.: 0 AF XY: 0.353 AC XY: 16823 AN XY: 47660

African (AFR) AF: 0.284 AC: 7410 AN: 26080

American (AMR) AF: 0.305 AC: 2670 AN: 8746

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1238 AN: 2800

East Asian (EAS) AF: 0.199 AC: 747 AN: 3746

South Asian (SAS) AF: 0.487 AC: 1414 AN: 2906

European-Finnish (FIN) AF: 0.142 AC: 520 AN: 3672

Middle Eastern (MID) AF: 0.296 AC: 45 AN: 152

European-Non Finnish (NFE) AF: 0.440 AC: 23195 AN: 52664

Other (OTH) AF: 0.357 AC: 477 AN: 1336

Alfa AF: 0.0947 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 (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;