rs775324034

chr2-232847517-A-AGchr2-232847517-A-AGCAGCAGCAGCAGCAGCTGCCGCAGchr2-232847517-A-AGCAGCAGCAGCAGCTGCCGCAGchr2-232847517-A-AGCAGCAGCTGCCGCAG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BA1

The NM_001103146.3(GIGYF2):c.3630_3631insG(p.Gln1211AlafsTer46) variant causes a frameshift change. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P1210P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.17 (237 hom., cov: 0)
  • Exomes 𝑓: 0.12 (1775 hom.)
• Consequence: GIGYF2 NM_001103146.3 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.44

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 2-232847517-A-AG is Benign according to our data. Variant chr2-232847517-A-AG is described in ClinVar as [Likely_benign]. Clinvar id is 402900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIGYF2	NM_001103146.3	c.3630_3631insG	p.Gln1211AlafsTer46	frameshift_variant	27/29	ENST00000373563.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIGYF2	ENST00000373563.9	c.3630_3631insG	p.Gln1211AlafsTer46	frameshift_variant	27/29	1	NM_001103146.3	P4

Frequencies

GnomAD3 genomes AF: 0.173 AC: 5019 AN: 28964 Hom.: 237 Cov.: 0

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.0339 AC: 7827 AN: 230696 Hom.: 334 AF XY: 0.0342 AC XY: 4313 AN XY: 125968

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.129

Gnomad SAS exome AF: 0.0578

Gnomad FIN exome AF: 0.0452

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.120 AC: 46437 AN: 386888 Hom.: 1775 Cov.: 0 AF XY: 0.122 AC XY: 23962 AN XY: 196702

Gnomad4 AFR exome AF: 0.0313

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.458

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.352

Gnomad4 NFE exome AF: 0.0763

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.173 AC: 5019 AN: 28976 Hom.: 237 Cov.: 0 AF XY: 0.188 AC XY: 2792 AN XY: 14836

Gnomad4 AFR AF: 0.0448

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.170

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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: 39.59% east asian with 179 homozygotes in ExAC (VQSRTrancheINDEL96.00to97.00) -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs775324034; hg19: chr2-233712227; COSMIC: COSV101004226; COSMIC: COSV101004226;