rs34424361

Variant names:

• chr2-232856815-G-A
• rs34424361
• NM_001103146.3:c.3855G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001103146.3(GIGYF2):​c.3855G>A​(p.Ser1285Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,144 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 32)
  • Exomes 𝑓: 0.018 (304 hom.)
• Consequence: GIGYF2 NM_001103146.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.840
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-232856815-G-A is Benign according to our data. Variant chr2-232856815-G-A is described in ClinVar as Benign. ClinVar VariationId is 3038024.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0155 (2365/152182) while in subpopulation NFE AF = 0.0193 (1311/68002). AF 95% confidence interval is 0.0184. There are 28 homozygotes in GnomAd4. There are 1288 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2365 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.3855G>A	p.Ser1285Ser	synonymous_variant	Exon 29 of 29	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.3855G>A	p.Ser1285Ser	synonymous_variant	Exon 29 of 29	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2367 AN: 152064 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0168 AC: 4234 AN: 251366 AF XY: 0.0168

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0589

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.0184 AC: 26888 AN: 1460962 Hom.: 304 Cov.: 30 AF XY: 0.0181 AC XY: 13126 AN XY: 726860

African (AFR) AF: 0.00254 AC: 85 AN: 33466

American (AMR) AF: 0.0120 AC: 535 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00612 AC: 160 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00519 AC: 448 AN: 86250

European-Finnish (FIN) AF: 0.0579 AC: 3093 AN: 53414

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.0194 AC: 21586 AN: 1111134

Other (OTH) AF: 0.0158 AC: 952 AN: 60376

GnomAD4 genome AF: 0.0155 AC: 2365 AN: 152182 Hom.: 28 Cov.: 32 AF XY: 0.0173 AC XY: 1288 AN XY: 74398

African (AFR) AF: 0.00323 AC: 134 AN: 41520

American (AMR) AF: 0.0172 AC: 263 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4824

European-Finnish (FIN) AF: 0.0563 AC: 596 AN: 10586

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0193 AC: 1311 AN: 68002

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.0171 Hom.: 48

Bravo AF: 0.0117

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GIGYF2-related disorder Benign:1

Apr 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.1
DANN	Benign	0.87
PhyloP100		-0.84
PromoterAI		-0.0020	Neutral
Mutation Taster		=100/0	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: rs34424361; hg19: chr2-233721525;