chr2-232794843-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001103146.3(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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 237 hom., cov: 32)

Exomes 𝑓: 0.032 ( 2190 hom. )

Consequence

GIGYF2
NM_001103146.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.66

Publications

24 publications found

Variant links:

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

GIGYF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 1295070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3 link	c.1378C>A	p.Pro460Thr	missense_variant	Exon 13 of 29	ENST00000373563.9	NP_001096616.1	Q6Y7W6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9 link	c.1378C>A	p.Pro460Thr	missense_variant	Exon 13 of 29	1	NM_001103146.3	ENSP00000362664.5		Q6Y7W6-1

Frequencies

GnomAD3 genomes

AF:

0.0330

AC:

5020

AN:

152108

Hom.:

237

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0547

AC:

13736

AN:

251304

AF XY:

0.0540

show subpopulations

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 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.:

AF XY:

0.0335

AC XY:

24324

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.00678

AC:

227

AN:

33466

American (AMR)

AF:

0.0704

AC:

3146

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0180

AC:

470

AN:

26130

East Asian (EAS)

AF:

0.251

AC:

9961

AN:

39676

South Asian (SAS)

AF:

0.0787

AC:

6787

AN:

86246

European-Finnish (FIN)

AF:

0.0711

AC:

3799

AN:

53420

Middle Eastern (MID)

AF:

0.0442

AC:

255

AN:

5766

European-Non Finnish (NFE)

AF:

0.0183

AC:

20390

AN:

1111530

Other (OTH)

AF:

0.0351

AC:

2119

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2481

4962

7442

9923

12404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

958

1916

2874

3832

4790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0330

AC:

5021

AN:

152226

Hom.:

237

Cov.:

AF XY:

0.0374

AC XY:

2783

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00700

AC:

291

AN:

41568

American (AMR)

AF:

0.0492

AC:

752

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3470

East Asian (EAS)

AF:

0.230

AC:

1190

AN:

5164

South Asian (SAS)

AF:

0.0862

AC:

415

AN:

4816

European-Finnish (FIN)

AF:

0.0760

AC:

805

AN:

10592

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0204

AC:

1387

AN:

68012

Other (OTH)

AF:

0.0284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

229

457

686

914

1143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0260

Hom.:

519

Bravo

AF:

0.0310

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0184

AC:

ESP6500AA

AF:

0.00749

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GIGYF2-related disorder

Benign:1

Jul 17, 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

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

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

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

PhyloP100

1.7

PrimateAI

Benign

0.33

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

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.043

gMVP

0.23

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over