2-232847538-G-A

Variant names:

• chr2-232847538-G-A
• rs12328151
• NM_001103146.3:c.3651G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001103146.3(GIGYF2):​c.3651G>A​(p.Pro1217Pro) 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
• Publications: 11 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 -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 VariationId is 518339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103146.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	NM_001103146.3	MANE Select	c.3651G>A	p.Pro1217Pro	synonymous	Exon 27 of 29	NP_001096616.1
	GIGYF2	NM_001103147.2		c.3714G>A	p.Pro1238Pro	synonymous	Exon 29 of 31	NP_001096617.1
	GIGYF2	NM_015575.4		c.3651G>A	p.Pro1217Pro	synonymous	Exon 29 of 31	NP_056390.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.3651G>A	p.Pro1217Pro	synonymous	Exon 27 of 29	ENSP00000362664.5
	GIGYF2	ENST00000409451.7	TSL:1	c.3714G>A	p.Pro1238Pro	synonymous	Exon 29 of 31	ENSP00000387170.3
	GIGYF2	ENST00000409547.5	TSL:1	c.3651G>A	p.Pro1217Pro	synonymous	Exon 29 of 31	ENSP00000386537.1

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

GnomAD2 exomes AF: 0.187 AC: 44473 AN: 237454 AF XY: 0.186

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 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

African (AFR) AF: 0.0527 AC: 1750 AN: 33196

American (AMR) AF: 0.157 AC: 6985 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7443 AN: 25532

East Asian (EAS) AF: 0.0975 AC: 3848 AN: 39474

South Asian (SAS) AF: 0.0930 AC: 7967 AN: 85670

European-Finnish (FIN) AF: 0.279 AC: 14553 AN: 52242

Middle Eastern (MID) AF: 0.218 AC: 953 AN: 4370

European-Non Finnish (NFE) AF: 0.209 AC: 230944 AN: 1104042

Other (OTH) AF: 0.195 AC: 11642 AN: 59612

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

African (AFR) AF: 0.0548 AC: 2256 AN: 41200

American (AMR) AF: 0.167 AC: 2534 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 977 AN: 3392

East Asian (EAS) AF: 0.111 AC: 571 AN: 5142

South Asian (SAS) AF: 0.0944 AC: 452 AN: 4788

European-Finnish (FIN) AF: 0.281 AC: 2959 AN: 10530

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14797 AN: 67678

Other (OTH) AF: 0.196 AC: 411 AN: 2092

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

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 10, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.1
DANN	Benign	0.45
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12328151; hg19: chr2-233712248;