rs748538823

Variant names:

• chr2-232819834-C-A
• rs748538823
• NM_001103146.3:c.2378C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-232819834-C-A
• chr2-232819834-C-G
• chr2-232819834-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.06
• Publications: 0 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: 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	c.2378C>A	p.Ala793Asp	missense_variant	Exon 21 of 29	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.2378C>A	p.Ala793Asp	missense_variant	Exon 21 of 29	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 8.73e-7 AC: 1 AN: 1145544 Hom.: 0 Cov.: 19 AF XY: 0.00000175 AC XY: 1 AN XY: 570382

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

African (AFR) AF: 0.00 AC: 0 AN: 24834

American (AMR) AF: 0.00 AC: 0 AN: 37060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17230

East Asian (EAS) AF: 0.00 AC: 0 AN: 18622

South Asian (SAS) AF: 0.00 AC: 0 AN: 81000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4074

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 885206

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 26

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	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
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	D
LIST_S2	Uncertain	0.95	D;.;.;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
PhyloP100		5.1
PrimateAI	Pathogenic	0.83	D
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	D
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

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: rs748538823; hg19: chr2-233684544;