Genetic Variant GIGYF2:c.268-11_268-6dupTTTTTT (chr2-232756197-C-CTTTTTT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001103146.3(GIGYF2):c.268-11_268-6dupTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000088 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

GIGYF2
NM_001103146.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.876

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3 link	c.268-11_268-6dupTTTTTT		splice_region_variant, intron_variant	Intron 5 of 28	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.268-26_268-25insTTTTTT		intron_variant	Intron 5 of 28	1	NM_001103146.3	ENSP00000362664.5		Q6Y7W6-1

Frequencies

GnomAD3 genomes

AF:

0.0000876

AC:

AN:

102710

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000384

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000358

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000114

Gnomad OTH

AF:

0.000759

GnomAD4 exome

AF:

0.000250

AC:

152

AN:

607800

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

AN XY:

322302

show subpopulations

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

African (AFR)

AF:

0.000135

AC:

AN:

14866

American (AMR)

AF:

0.000505

AC:

AN:

25766

Ashkenazi Jewish (ASJ)

AF:

0.000187

AC:

AN:

16078

East Asian (EAS)

AF:

0.000255

AC:

AN:

31426

South Asian (SAS)

AF:

0.000746

AC:

AN:

48280

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

37006

Middle Eastern (MID)

AF:

0.000441

AC:

AN:

2268

European-Non Finnish (NFE)

AF:

0.000194

AC:

AN:

402376

Other (OTH)

AF:

0.000135

AC:

AN:

29734

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.360

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000877

AC:

AN:

102676

Hom.:

Cov.:

AF XY:

0.0000841

AC XY:

AN XY:

47570

show subpopulations

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

African (AFR)

AF:

0.0000384

AC:

AN:

26038

American (AMR)

AF:

0.00

AC:

AN:

8742

Ashkenazi Jewish (ASJ)

AF:

0.000358

AC:

AN:

2792

East Asian (EAS)

AF:

0.00

AC:

AN:

3746

South Asian (SAS)

AF:

0.00

AC:

AN:

2896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.000114

AC:

AN:

52572

Other (OTH)

AF:

0.000752

AC:

AN:

1330

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.006183), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.353

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.88

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-232756197-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over