rs34424361

chr2-232856815-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001103146.3(GIGYF2):c.3855G>A(p.Ser1285=) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 32)
  • Exomes 𝑓: 0.018 (304 hom.)
• Consequence: GIGYF2 NM_001103146.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.840

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]

ACMG classification

Verdict is Benign. Variant got -15 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 id is 3038024.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-232856815-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2367 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIGYF2	NM_001103146.3	c.3855G>A	p.Ser1285=	synonymous_variant	29/29	ENST00000373563.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIGYF2	ENST00000373563.9	c.3855G>A	p.Ser1285=	synonymous_variant	29/29	1	NM_001103146.3	P4

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

GnomAD3 exomes AF: 0.0168 AC: 4234 AN: 251366 Hom.: 62 AF XY: 0.0168 AC XY: 2286 AN XY: 135850

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 SAS exome AF: 0.00578

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

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00519

Gnomad4 FIN exome AF: 0.0579

Gnomad4 NFE exome AF: 0.0194

Gnomad4 OTH exome AF: 0.0158

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

Gnomad4 AFR AF: 0.00323

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0563

Gnomad4 NFE AF: 0.0193

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0163 Hom.: 12

Bravo AF: 0.0117

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GIGYF2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs34424361; hg19: chr2-233721525;