rs118203903

Variant names:

• chr2-232809731-C-G
• rs118203903
• NM_001103146.3:c.1818C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001103146.3(GIGYF2):​c.1818C>G​(p.Asp606Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GIGYF2 NM_001103146.3 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 1.96
• Publications: 3 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: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

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.1818C>G	p.Asp606Glu	missense	Exon 16 of 29	NP_001096616.1	Q6Y7W6-1
	GIGYF2	NM_001103147.2		c.1881C>G	p.Asp627Glu	missense	Exon 18 of 31	NP_001096617.1	Q6Y7W6-3
	GIGYF2	NM_015575.4		c.1818C>G	p.Asp606Glu	missense	Exon 18 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.1818C>G	p.Asp606Glu	missense	Exon 16 of 29	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.1881C>G	p.Asp627Glu	missense	Exon 18 of 31	ENSP00000387170.3	Q6Y7W6-3
	GIGYF2	ENST00000409547.5	TSL:1	c.1818C>G	p.Asp606Glu	missense	Exon 18 of 31	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Parkinson disease 11, autosomal dominant, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.18	D
PhyloP100		2.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.72		Loss of loop (P = 0.0073)
MVP		0.88
MPC		0.97
ClinPred		0.92	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.67
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs118203903; hg19: chr2-233674441;