rs147476925

Variant names:

• chr2-232756224-G-A
• rs147476925
• NM_001103146.3:c.269G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-232756224-G-A
• chr2-232756224-G-T

Variant summary

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

The NM_001103146.3(GIGYF2):​c.269G>A​(p.Arg90Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GIGYF2 NM_001103146.3 missense, splice_region
• Scores: Splicing: ADA: 0.003853
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.269G>A	p.Arg90Lys	missense_variant, splice_region_variant	Exon 6 of 29	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.269G>A	p.Arg90Lys	missense_variant, splice_region_variant	Exon 6 of 29	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes AF: 0.0000207 AC: 2 AN: 96528 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000197

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000122 AC: 1 AN: 821600 Hom.: 0 Cov.: 18 AF XY: 0.00000237 AC XY: 1 AN XY: 422788

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19302

American (AMR) AF: 0.00 AC: 0 AN: 28788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19102

East Asian (EAS) AF: 0.00 AC: 0 AN: 32122

South Asian (SAS) AF: 0.00 AC: 0 AN: 53056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2678

European-Non Finnish (NFE) AF: 0.00000170 AC: 1 AN: 587604

Other (OTH) AF: 0.00 AC: 0 AN: 37090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000207 AC: 2 AN: 96528 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 44388

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000420 AC: 1 AN: 23810

American (AMR) AF: 0.00 AC: 0 AN: 7320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2712

East Asian (EAS) AF: 0.00 AC: 0 AN: 3590

South Asian (SAS) AF: 0.00 AC: 0 AN: 2922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 146

European-Non Finnish (NFE) AF: 0.0000197 AC: 1 AN: 50842

Other (OTH) AF: 0.00 AC: 0 AN: 1208

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	.;D;T;.;.;.;.;D;T;.;.;T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;.;T;.;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.50	D
PhyloP100		10
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	.;N;D;N;D;D;D;N;D;N;N;D;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.019	.;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.012	.;B;.;.;.;.;.;B;.;.;.;.;.
Vest4		0.53
MutPred		0.26		Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);Gain of ubiquitination at R90 (P = 0.0094);
MVP		0.83
MPC		0.35
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.76
gMVP		0.44
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0039
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.020		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: rs147476925; hg19: chr2-233620934;