Genetic Variant GIGYF2:c.268-7_268-6dupTT (chr2-232756197-C-CTT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001103146.3(GIGYF2):c.268-7_268-6dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0089 ( 14 hom., cov: 0)

Exomes 𝑓: 0.037 ( 32 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.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00891 (915/102646) while in subpopulation SAS AF = 0.0211 (61/2896). AF 95% confidence interval is 0.0168. There are 14 homozygotes in GnomAd4. There are 429 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 915 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3 link	c.268-7_268-6dupTT		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_268-25insTT		intron_variant	Intron 5 of 28	1	NM_001103146.3	ENSP00000362664.5		Q6Y7W6-1

Frequencies

GnomAD3 genomes

AF:

0.00891

AC:

915

AN:

102680

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00703

Gnomad AMI

AF:

0.00546

Gnomad AMR

AF:

0.00722

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00478

Gnomad SAS

AF:

0.0209

Gnomad FIN

AF:

0.00544

Gnomad MID

AF:

0.0176

Gnomad NFE

AF:

0.00963

Gnomad OTH

AF:

0.0121

GnomAD4 exome

AF:

0.0367

AC:

21870

AN:

596562

Hom.:

Cov.:

AF XY:

0.0373

AC XY:

11792

AN XY:

315988

show subpopulations

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

African (AFR)

AF:

0.0245

AC:

360

AN:

14668

American (AMR)

AF:

0.0267

AC:

681

AN:

25466

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

634

AN:

15800

East Asian (EAS)

AF:

0.0138

AC:

428

AN:

31080

South Asian (SAS)

AF:

0.0621

AC:

2923

AN:

47036

European-Finnish (FIN)

AF:

0.0277

AC:

1009

AN:

36420

Middle Eastern (MID)

AF:

0.0296

AC:

AN:

2226

European-Non Finnish (NFE)

AF:

0.0373

AC:

14705

AN:

394750

Other (OTH)

AF:

0.0365

AC:

1064

AN:

29116

⚠️ 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

1390

2780

4169

5559

6949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00891

AC:

915

AN:

102646

Hom.:

Cov.:

AF XY:

0.00902

AC XY:

429

AN XY:

47562

show subpopulations

African (AFR)

AF:

0.00703

AC:

183

AN:

26040

American (AMR)

AF:

0.00721

AC:

AN:

8736

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

2792

East Asian (EAS)

AF:

0.00481

AC:

AN:

3746

South Asian (SAS)

AF:

0.0211

AC:

AN:

2896

European-Finnish (FIN)

AF:

0.00544

AC:

AN:

3676

Middle Eastern (MID)

AF:

0.0200

AC:

AN:

150

European-Non Finnish (NFE)

AF:

0.00963

AC:

506

AN:

52546

Other (OTH)

AF:

0.0120

AC:

AN:

1332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00247

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

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

Publications

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2-232756197-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTT

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