Genetic Variant GIGYF2:c.268-6delT (chr2-232756197-CT-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001103146.3(GIGYF2):c.268-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.086 ( 407 hom., cov: 0)

Exomes 𝑓: 0.12 ( 6 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: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3 link	c.268-6delT		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.268-25delT		intron_variant	Intron 5 of 28	1	NM_001103146.3	ENSP00000362664.5		Q6Y7W6-1

Frequencies

GnomAD3 genomes

AF:

0.0864

AC:

8860

AN:

102604

Hom.:

408

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.00137

Gnomad AMR

AF:

0.0834

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.0640

Gnomad FIN

AF:

0.0237

Gnomad MID

AF:

0.0291

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.0693

GnomAD4 exome

AF:

0.121

AC:

71627

AN:

592778

Hom.:

Cov.:

AF XY:

0.117

AC XY:

36883

AN XY:

313970

show subpopulations

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

African (AFR)

AF:

0.211

AC:

3084

AN:

14598

American (AMR)

AF:

0.111

AC:

2796

AN:

25302

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

1776

AN:

15652

East Asian (EAS)

AF:

0.202

AC:

6134

AN:

30434

South Asian (SAS)

AF:

0.0877

AC:

4148

AN:

47298

European-Finnish (FIN)

AF:

0.125

AC:

4476

AN:

35948

Middle Eastern (MID)

AF:

0.120

AC:

265

AN:

2210

European-Non Finnish (NFE)

AF:

0.115

AC:

45063

AN:

392422

Other (OTH)

AF:

0.134

AC:

3885

AN:

28914

⚠️ 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: 0.333

Heterozygous variant carriers

4421

8842

13263

17684

22105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0864

AC:

8861

AN:

102572

Hom.:

407

Cov.:

AF XY:

0.0904

AC XY:

4297

AN XY:

47530

show subpopulations

African (AFR)

AF:

0.247

AC:

6422

AN:

25968

American (AMR)

AF:

0.0837

AC:

731

AN:

8734

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

2792

East Asian (EAS)

AF:

0.175

AC:

652

AN:

3734

South Asian (SAS)

AF:

0.0642

AC:

186

AN:

2896

European-Finnish (FIN)

AF:

0.0237

AC:

AN:

3676

Middle Eastern (MID)

AF:

0.0329

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.0124

AC:

654

AN:

52562

Other (OTH)

AF:

0.0686

AC:

AN:

1326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

269

538

808

1077

1346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0120

Hom.:

144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.88

Mutation Taster

=100/0

polymorphism

(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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2-232756197-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTT

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