rs2305137

Positions:

• chr2-232847339-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001103146.3(GIGYF2):​c.3461-9G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,606,238 control chromosomes in the GnomAD database, including 330,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32610 hom., cov: 32)
  • Exomes 𝑓: 0.64 (298297 hom.)
• Consequence: GIGYF2 NM_001103146.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003926
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.901

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-232847339-G-A is Benign according to our data. Variant chr2-232847339-G-A is described in ClinVar as [Benign]. Clinvar id is 518337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232847339-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIGYF2	NM_001103146.3	c.3461-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000373563.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIGYF2	ENST00000373563.9	c.3461-9G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001103146.3	P4

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99004 AN: 151850 Hom.: 32585 Cov.: 32

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.667

GnomAD3 exomes AF: 0.642 AC: 161496 AN: 251378 Hom.: 53636 AF XY: 0.626 AC XY: 85067 AN XY: 135868

Gnomad AFR exome AF: 0.624

Gnomad AMR exome AF: 0.742

Gnomad ASJ exome AF: 0.664

Gnomad EAS exome AF: 0.673

Gnomad SAS exome AF: 0.362

Gnomad FIN exome AF: 0.766

Gnomad NFE exome AF: 0.660

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.635 AC: 923521 AN: 1454270 Hom.: 298297 Cov.: 34 AF XY: 0.627 AC XY: 454117 AN XY: 723992

Gnomad4 AFR exome AF: 0.622

Gnomad4 AMR exome AF: 0.737

Gnomad4 ASJ exome AF: 0.669

Gnomad4 EAS exome AF: 0.709

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.764

Gnomad4 NFE exome AF: 0.643

Gnomad4 OTH exome AF: 0.626

GnomAD4 genome AF: 0.652 AC: 99082 AN: 151968 Hom.: 32610 Cov.: 32 AF XY: 0.654 AC XY: 48558 AN XY: 74272

Gnomad4 AFR AF: 0.626

Gnomad4 AMR AF: 0.696

Gnomad4 ASJ AF: 0.665

Gnomad4 EAS AF: 0.668

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.768

Gnomad4 NFE AF: 0.658

Gnomad4 OTH AF: 0.659

Alfa AF: 0.659 Hom.: 14318

Bravo AF: 0.656

Asia WGS AF: 0.498 AC: 1733 AN: 3478

EpiCase AF: 0.651

EpiControl AF: 0.656

ClinVar

Significance: Benign

Submissions summary: Benign:4

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, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Mar 21, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.034
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.0020
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: rs2305137; hg19: chr2-233712049;