rs2289912

Positions:

• chr2-232794843-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000373563.9(GIGYF2):​c.1378C>A​(p.Pro460Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 1,613,548 control chromosomes in the GnomAD database, including 2,427 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.033 (237 hom., cov: 32)
  • Exomes 𝑓: 0.032 (2190 hom.)
• Consequence: GIGYF2 ENST00000373563.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.66

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011896789).
• BP6: Variant 2-232794843-C-A is Benign according to our data. Variant chr2-232794843-C-A is described in ClinVar as [Benign]. Clinvar id is 1295070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232794843-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.1378C>A	p.Pro460Thr	missense_variant	13/29	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.1378C>A	p.Pro460Thr	missense_variant	13/29	1	NM_001103146.3	ENSP00000362664	P4

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5020 AN: 152108 Hom.: 237 Cov.: 32

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.0861

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0547 AC: 13736 AN: 251304 Hom.: 805 AF XY: 0.0540 AC XY: 7339 AN XY: 135804

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.0741

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.225

Gnomad SAS exome AF: 0.0798

Gnomad FIN exome AF: 0.0705

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0452

GnomAD4 exome AF: 0.0323 AC: 47154 AN: 1461322 Hom.: 2190 Cov.: 31 AF XY: 0.0335 AC XY: 24324 AN XY: 727010

Gnomad4 AFR exome AF: 0.00678

Gnomad4 AMR exome AF: 0.0704

Gnomad4 ASJ exome AF: 0.0180

Gnomad4 EAS exome AF: 0.251

Gnomad4 SAS exome AF: 0.0787

Gnomad4 FIN exome AF: 0.0711

Gnomad4 NFE exome AF: 0.0183

Gnomad4 OTH exome AF: 0.0351

GnomAD4 genome AF: 0.0330 AC: 5021 AN: 152226 Hom.: 237 Cov.: 32 AF XY: 0.0374 AC XY: 2783 AN XY: 74402

Gnomad4 AFR AF: 0.00700

Gnomad4 AMR AF: 0.0492

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.0862

Gnomad4 FIN AF: 0.0760

Gnomad4 NFE AF: 0.0204

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0238 Hom.: 175

Bravo AF: 0.0310

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.0198 AC: 170

ExAC AF: 0.0524 AC: 6359

Asia WGS AF: 0.133 AC: 462 AN: 3478

EpiCase AF: 0.0204

EpiControl AF: 0.0208

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

GIGYF2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 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
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.10	.;T;.;T;T;.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;.;.;D;D;D;D;D
MetaRNN	Benign	0.0012	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.71	P;P;P;P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	.;N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.13	.;T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T
Polyphen		0.012	.;B;.;B;.;.;.;.
Vest4		0.14
MPC		0.56
ClinPred		0.011	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs2289912; hg19: chr2-233659553; COSMIC: COSV65247241; COSMIC: COSV65247241;