chr2-232847516-CACA-C

Variant names:

• chr2-232847516-CACA-C
• rs10555297
• NM_001103146.3:c.3630_3632delACA

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_001103146.3(GIGYF2):​c.3630_3632delACA​(p.Gln1211del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.574 in 1,526,600 control chromosomes in the GnomAD database, including 244,405 homozygotes. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P1210P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.61 (25547 hom., cov: 0)
  • Exomes 𝑓: 0.57 (218858 hom.)
• Consequence: GIGYF2 NM_001103146.3 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.44
• Publications: 24 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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001103146.3
• BP6: Variant 2-232847516-CACA-C is Benign according to our data. Variant chr2-232847516-CACA-C is described in ClinVar as Benign. ClinVar VariationId is 518338.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.3630_3632delACA	p.Gln1211del	disruptive_inframe_deletion	Exon 27 of 29	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.3630_3632delACA	p.Gln1211del	disruptive_inframe_deletion	Exon 27 of 29	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes AF: 0.612 AC: 87265 AN: 142576 Hom.: 25523 Cov.: 0

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.550

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.628

GnomAD2 exomes AF: 0.557 AC: 129291 AN: 232056 AF XY: 0.541

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.654

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.505

Gnomad FIN exome AF: 0.694

Gnomad NFE exome AF: 0.576

Gnomad OTH exome AF: 0.552

GnomAD4 exome AF: 0.570 AC: 789195 AN: 1383896 Hom.: 218858 AF XY: 0.562 AC XY: 386735 AN XY: 688594

African (AFR) AF: 0.608 AC: 20117 AN: 33062

American (AMR) AF: 0.644 AC: 27878 AN: 43304

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 15907 AN: 25372

East Asian (EAS) AF: 0.456 AC: 17981 AN: 39448

South Asian (SAS) AF: 0.272 AC: 22391 AN: 82246

European-Finnish (FIN) AF: 0.672 AC: 34599 AN: 51466

Middle Eastern (MID) AF: 0.480 AC: 2122 AN: 4420

European-Non Finnish (NFE) AF: 0.588 AC: 616189 AN: 1047494

Other (OTH) AF: 0.561 AC: 32011 AN: 57084

GnomAD4 genome AF: 0.612 AC: 87347 AN: 142704 Hom.: 25547 Cov.: 0 AF XY: 0.613 AC XY: 42699 AN XY: 69682

African (AFR) AF: 0.615 AC: 24977 AN: 40594

American (AMR) AF: 0.647 AC: 9223 AN: 14248

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2140 AN: 3332

East Asian (EAS) AF: 0.537 AC: 2203 AN: 4104

South Asian (SAS) AF: 0.311 AC: 1270 AN: 4080

European-Finnish (FIN) AF: 0.702 AC: 7001 AN: 9974

Middle Eastern (MID) AF: 0.546 AC: 143 AN: 262

European-Non Finnish (NFE) AF: 0.611 AC: 38684 AN: 63308

Other (OTH) AF: 0.621 AC: 1228 AN: 1976

Alfa AF: 0.545 Hom.: 1638

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson disease 11, autosomal dominant, susceptibility to Benign:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=65/35	polymorphism

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: rs10555297; hg19: chr2-233712226; COSMIC: COSV65246203; COSMIC: COSV65246203;