rs7563724

Variant names:

• chr2-232847517-A-G
• rs7563724
• NM_001103146.3:c.3630A>G
• GIGYF2 p.Pro1210Pro

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001103146.3(GIGYF2):​c.3630A>G​(p.Pro1210Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (83 hom.)
  • Failed GnomAD Quality Control
• Consequence: GIGYF2 NM_001103146.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0630
• Publications: 8 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-232847517-A-G is Benign according to our data. Variant chr2-232847517-A-G is described in ClinVar as Benign. ClinVar VariationId is 3039772.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.063 with no splicing effect.
• BS2: High AC in GnomAd4 at 17 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.3630A>G	p.Pro1210Pro	synonymous	Exon 27 of 29	NP_001096616.1	Q6Y7W6-1
	GIGYF2	NM_001103147.2		c.3693A>G	p.Pro1231Pro	synonymous	Exon 29 of 31	NP_001096617.1	Q6Y7W6-3
	GIGYF2	NM_015575.4		c.3630A>G	p.Pro1210Pro	synonymous	Exon 29 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.3630A>G	p.Pro1210Pro	synonymous	Exon 27 of 29	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.3693A>G	p.Pro1231Pro	synonymous	Exon 29 of 31	ENSP00000387170.3	Q6Y7W6-3
	GIGYF2	ENST00000409547.5	TSL:1	c.3630A>G	p.Pro1210Pro	synonymous	Exon 29 of 31	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes AF: 0.000587 AC: 17 AN: 28976 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000369

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000460

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00735 AC: 1696 AN: 230696 AF XY: 0.00605

Gnomad AFR exome AF: 0.00825

Gnomad AMR exome AF: 0.00423

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.0287

Gnomad FIN exome AF: 0.00880

Gnomad NFE exome AF: 0.00617

Gnomad OTH exome AF: 0.00519

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00119 AC: 458 AN: 386294 Hom.: 83 Cov.: 0 AF XY: 0.00126 AC XY: 248 AN XY: 196418

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

African (AFR) AF: 0.000276 AC: 2 AN: 7242

American (AMR) AF: 0.000865 AC: 8 AN: 9250

Ashkenazi Jewish (ASJ) AF: 0.000225 AC: 1 AN: 4450

East Asian (EAS) AF: 0.000195 AC: 4 AN: 20552

South Asian (SAS) AF: 0.000369 AC: 18 AN: 48826

European-Finnish (FIN) AF: 0.0250 AC: 256 AN: 10256

Middle Eastern (MID) AF: 0.00456 AC: 7 AN: 1534

European-Non Finnish (NFE) AF: 0.000510 AC: 137 AN: 268412

Other (OTH) AF: 0.00159 AC: 25 AN: 15772

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000586 AC: 17 AN: 28988 Hom.: 0 Cov.: 0 AF XY: 0.000741 AC XY: 11 AN XY: 14842

African (AFR) AF: 0.00108 AC: 7 AN: 6460

American (AMR) AF: 0.00138 AC: 4 AN: 2898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 474

East Asian (EAS) AF: 0.000371 AC: 1 AN: 2698

South Asian (SAS) AF: 0.00 AC: 0 AN: 2706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 88

European-Non Finnish (NFE) AF: 0.000460 AC: 5 AN: 10870

Other (OTH) AF: 0.00 AC: 0 AN: 358

Alfa AF: 0.345 Hom.: 2531

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GIGYF2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.26
PhyloP100		-0.063
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=23/77	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs7563724;

hg19: chr2-233712227;

COSMIC: COSV65247736;

COSMIC: COSV65247736;