rs12328151

Positions:

• chr2-232847538-G-A
• chr2-232847538-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001103146.3(GIGYF2):​c.3651G>A​(p.Pro1217=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,599,718 control chromosomes in the GnomAD database, including 32,803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2607 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30196 hom.)
• Consequence: GIGYF2 NM_001103146.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.437

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-232847538-G-A is Benign according to our data. Variant chr2-232847538-G-A is described in ClinVar as [Benign]. Clinvar id is 518339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232847538-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.437 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.3651G>A	p.Pro1217=	synonymous_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.3651G>A	p.Pro1217=	synonymous_variant	27/29	1	NM_001103146.3	ENSP00000362664	P4

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25157 AN: 151076 Hom.: 2610 Cov.: 32

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0954

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.198

GnomAD3 exomes AF: 0.187 AC: 44473 AN: 237454 Hom.: 4657 AF XY: 0.186 AC XY: 24276 AN XY: 130298

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.292

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.0897

Gnomad FIN exome AF: 0.293

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.198 AC: 286085 AN: 1448526 Hom.: 30196 Cov.: 65 AF XY: 0.196 AC XY: 141278 AN XY: 720744

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.0975

Gnomad4 SAS exome AF: 0.0930

Gnomad4 FIN exome AF: 0.279

Gnomad4 NFE exome AF: 0.209

Gnomad4 OTH exome AF: 0.195

GnomAD4 genome AF: 0.166 AC: 25150 AN: 151192 Hom.: 2607 Cov.: 32 AF XY: 0.167 AC XY: 12377 AN XY: 73894

Gnomad4 AFR AF: 0.0548

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.0944

Gnomad4 FIN AF: 0.281

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.196

Alfa AF: 0.197 Hom.: 421

Bravo AF: 0.155

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parkinson disease 11, autosomal dominant, susceptibility to Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.1
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs12328151; hg19: chr2-233712248;