rs371622656

Positions:

• chr2-232847515-C-CCG
• chr2-232847515-C-CCGCGT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_001103146.3(GIGYF2):​c.3629_3630insGC​(p.Gln1211fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,385,702 control chromosomes in the GnomAD database, including 2,014 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1210P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.058 (236 hom., cov: 30)
  • Exomes 𝑓: 0.036 (1778 hom.)
• Consequence: GIGYF2 NM_001103146.3 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0440

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 2-232847515-C-CCG is Benign according to our data. Variant chr2-232847515-C-CCG is described in ClinVar as [Likely_benign]. Clinvar id is 402899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.3629_3630insGC	p.Gln1211fs	frameshift_variant	27/29	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.3629_3630insGC	p.Gln1211fs	frameshift_variant	27/29	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes AF: 0.0577 AC: 5016 AN: 86914 Hom.: 236 Cov.: 30

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0896

Gnomad AMR AF: 0.0911

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.0914

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0550

GnomAD3 exomes AF: 0.0464 AC: 7524 AN: 162200 Hom.: 326 AF XY: 0.0455 AC XY: 4133 AN XY: 90768

Gnomad AFR exome AF: 0.00540

Gnomad AMR exome AF: 0.0787

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.159

Gnomad SAS exome AF: 0.0573

Gnomad FIN exome AF: 0.0794

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0345

GnomAD4 exome AF: 0.0357 AC: 46337 AN: 1298714 Hom.: 1778 Cov.: 61 AF XY: 0.0369 AC XY: 23920 AN XY: 647452

Gnomad4 AFR exome AF: 0.00693

Gnomad4 AMR exome AF: 0.0737

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.242

Gnomad4 SAS exome AF: 0.0826

Gnomad4 FIN exome AF: 0.0723

Gnomad4 NFE exome AF: 0.0211

Gnomad4 OTH exome AF: 0.0384

GnomAD4 genome AF: 0.0577 AC: 5016 AN: 86988 Hom.: 236 Cov.: 30 AF XY: 0.0655 AC XY: 2791 AN XY: 42634

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.0915

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.0375

Gnomad4 OTH AF: 0.0522

Alfa AF: 0.000373 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parkinson disease 11, autosomal dominant, susceptibility to Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Mar 26, 2015	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 23.92% East Asian, with 176 homozygotes (VQSRTrancheINDEL99.00to99.50) -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs371622656; hg19: chr2-233712225;