Genetic Variant NM_001103146.3:c.2378C>A (chr2-232819834-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_001103146.3(GIGYF2):c.2378C>A(p.Ala793Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000873 in 1,145,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A793V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 8.7e-7 ( 0 hom. )

Consequence

GIGYF2
NM_001103146.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.06

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-232819834-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216934.

BP4

Computational evidence support a benign effect (MetaRNN=0.38012376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3 link	c.2378C>A	p.Ala793Asp	missense_variant	Exon 21 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.2378C>A	p.Ala793Asp	missense_variant	Exon 21 of 29	1	NM_001103146.3	ENSP00000362664.5		Q6Y7W6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.73e-7

AC:

AN:

1145544

Hom.:

Cov.:

AF XY:

0.00000175

AC XY:

AN XY:

570382

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

24834

American (AMR)

AF:

0.00

AC:

AN:

37060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17230

East Asian (EAS)

AF:

0.00

AC:

AN:

18622

South Asian (SAS)

AF:

0.00

AC:

AN:

81000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4074

European-Non Finnish (NFE)

AF:

0.00000113

AC:

AN:

885206

Other (OTH)

AF:

0.00

AC:

AN:

42432

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;T;.;T;.;.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.;.;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.38

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.21

PhyloP100

5.1

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.1

.;N;N;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.52

.;T;T;T;T;T;D

Sift4G

Benign

0.55

T;T;T;T;T;T;T

Polyphen

0.98

.;D;.;D;.;.;.

Vest4

0.69

MutPred

0.32

.;Gain of relative solvent accessibility (P = 0.0479);.;Gain of relative solvent accessibility (P = 0.0479);.;.;.;

MVP

0.18

MPC

0.45

ClinPred

0.90

GERP RS

5.0

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.40

gMVP

0.33

Mutation Taster

=12/88

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over