rs118203904

Variant names:

• chr2-232790817-A-G
• rs118203904
• NM_001103146.3:c.832A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001103146.3(GIGYF2):​c.832A>G​(p.Ile278Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: GIGYF2 NM_001103146.3 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 1.25
• Publications: 7 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039897263).
• BS2: High AC in GnomAd4 at 10 Unknown,AD gene.

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.832A>G	p.Ile278Val	missense	Exon 10 of 29	NP_001096616.1	Q6Y7W6-1
	GIGYF2	NM_001103147.2		c.898A>G	p.Ile300Val	missense	Exon 12 of 31	NP_001096617.1	Q6Y7W6-3
	GIGYF2	NM_015575.4		c.832A>G	p.Ile278Val	missense	Exon 12 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.832A>G	p.Ile278Val	missense	Exon 10 of 29	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.898A>G	p.Ile300Val	missense	Exon 12 of 31	ENSP00000387170.3	Q6Y7W6-3
	GIGYF2	ENST00000409547.5	TSL:1	c.832A>G	p.Ile278Val	missense	Exon 12 of 31	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000235 AC: 59 AN: 251420 AF XY: 0.000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00316

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461820 Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00116 AC: 46 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111958

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.000181 AC: 22

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	Benign	0.059
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.46	T
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.34
Sift	Benign	0.47	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.83
MPC		0.27
ClinPred		0.033	T
GERP RS		4.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.032
gMVP		0.12
Mutation Taster		=1/99	disease causing

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: rs118203904; hg19: chr2-233655527;