rs2305138

Variant names:

• chr2-232796136-G-A
• rs2305138
• NM_001103146.3:c.1554G>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.1554G>A​(p.Glu518Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0655 in 1,599,972 control chromosomes in the GnomAD database, including 4,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (614 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3438 hom.)
• Consequence: GIGYF2 NM_001103146.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.05
• Publications: 16 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=-0.49).
• BP6: Variant 2-232796136-G-A is Benign according to our data. Variant chr2-232796136-G-A is described in ClinVar as Benign. ClinVar VariationId is 522283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	NM_001103146.3	MANE Select	c.1554G>A	p.Glu518Glu	synonymous	Exon 14 of 29	NP_001096616.1
	GIGYF2	NM_001103147.2		c.1617G>A	p.Glu539Glu	synonymous	Exon 16 of 31	NP_001096617.1
	GIGYF2	NM_015575.4		c.1554G>A	p.Glu518Glu	synonymous	Exon 16 of 31	NP_056390.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.1554G>A	p.Glu518Glu	synonymous	Exon 14 of 29	ENSP00000362664.5
	GIGYF2	ENST00000409451.7	TSL:1	c.1617G>A	p.Glu539Glu	synonymous	Exon 16 of 31	ENSP00000387170.3
	GIGYF2	ENST00000409547.5	TSL:1	c.1554G>A	p.Glu518Glu	synonymous	Exon 16 of 31	ENSP00000386537.1

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12062 AN: 152078 Hom.: 612 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.0700

Gnomad FIN AF: 0.0793

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0581

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.0708 AC: 17778 AN: 251254 AF XY: 0.0687

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0478

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.189

Gnomad FIN exome AF: 0.0805

Gnomad NFE exome AF: 0.0575

Gnomad OTH exome AF: 0.0545

GnomAD4 exome AF: 0.0640 AC: 92693 AN: 1447776 Hom.: 3438 Cov.: 27 AF XY: 0.0636 AC XY: 45874 AN XY: 721214

African (AFR) AF: 0.126 AC: 4191 AN: 33184

American (AMR) AF: 0.0470 AC: 2103 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 630 AN: 26072

East Asian (EAS) AF: 0.172 AC: 6801 AN: 39594

South Asian (SAS) AF: 0.0605 AC: 5196 AN: 85948

European-Finnish (FIN) AF: 0.0787 AC: 4203 AN: 53394

Middle Eastern (MID) AF: 0.0280 AC: 161 AN: 5748

European-Non Finnish (NFE) AF: 0.0595 AC: 65408 AN: 1099202

Other (OTH) AF: 0.0667 AC: 4000 AN: 59930

GnomAD4 genome AF: 0.0794 AC: 12079 AN: 152196 Hom.: 614 Cov.: 32 AF XY: 0.0807 AC XY: 6003 AN XY: 74402

African (AFR) AF: 0.120 AC: 4994 AN: 41508

American (AMR) AF: 0.0488 AC: 747 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.172 AC: 891 AN: 5170

South Asian (SAS) AF: 0.0696 AC: 336 AN: 4826

European-Finnish (FIN) AF: 0.0793 AC: 839 AN: 10584

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0581 AC: 3953 AN: 68022

Other (OTH) AF: 0.0681 AC: 144 AN: 2114

Alfa AF: 0.0648 Hom.: 1515

Bravo AF: 0.0814

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Parkinson disease 11, autosomal dominant, susceptibility to (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.9
DANN	Benign	0.52
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs2305138; hg19: chr2-233660846; COSMIC: COSV65247655; COSMIC: COSV65247655;