chr2-232847515-C-CCG

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_001103146.3(GIGYF2):c.3629_3630insGC(p.Gln1211HisfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,385,702 control chromosomes in the GnomAD database, including 2,014 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1210P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.058 ( 236 hom., cov: 30)

Exomes 𝑓: 0.036 ( 1778 hom. )

Consequence

GIGYF2
NM_001103146.3 frameshift

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0440

Publications

4 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: Benign. The variant received -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 2-232847515-C-CCG is Benign according to our data. Variant chr2-232847515-C-CCG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103146.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GIGYF2	NM_001103146.3	MANE Select	c.3629_3630insGC	p.Gln1211HisfsTer25	frameshift	Exon 27 of 29	NP_001096616.1
GIGYF2	NM_001103147.2		c.3692_3693insGC	p.Gln1232HisfsTer25	frameshift	Exon 29 of 31	NP_001096617.1
GIGYF2	NM_015575.4		c.3629_3630insGC	p.Gln1211HisfsTer25	frameshift	Exon 29 of 31	NP_056390.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.3629_3630insGC	p.Gln1211HisfsTer25	frameshift	Exon 27 of 29	ENSP00000362664.5
GIGYF2	ENST00000409451.7	TSL:1	c.3692_3693insGC	p.Gln1232HisfsTer25	frameshift	Exon 29 of 31	ENSP00000387170.3
GIGYF2	ENST00000409547.5	TSL:1	c.3629_3630insGC	p.Gln1211HisfsTer25	frameshift	Exon 29 of 31	ENSP00000386537.1

Frequencies

GnomAD3 genomes

AF:

0.0577

AC:

5016

AN:

86914

Hom.:

236

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.0896

Gnomad AMR

AF:

0.0911

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.286

Gnomad SAS

AF:

0.101

Gnomad FIN

AF:

0.151

Gnomad MID

AF:

0.0914

Gnomad NFE

AF:

0.0374

Gnomad OTH

AF:

0.0550

GnomAD2 exomes

AF:

0.0464

AC:

7524

AN:

162200

AF XY:

0.0455

show subpopulations

Gnomad AFR exome

AF:

0.00540

Gnomad AMR exome

AF:

0.0787

Gnomad ASJ exome

AF:

0.0195

Gnomad EAS exome

AF:

0.159

Gnomad FIN exome

AF:

0.0794

Gnomad NFE exome

AF:

0.0186

Gnomad OTH exome

AF:

0.0345

GnomAD4 exome

AF:

0.0357

AC:

46337

AN:

1298714

Hom.:

1778

Cov.:

AF XY:

0.0369

AC XY:

23920

AN XY:

647452

show subpopulations

African (AFR)

AF:

0.00693

AC:

226

AN:

32634

American (AMR)

AF:

0.0737

AC:

3079

AN:

41752

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

468

AN:

24228

East Asian (EAS)

AF:

0.242

AC:

9514

AN:

39354

South Asian (SAS)

AF:

0.0826

AC:

6709

AN:

81256

European-Finnish (FIN)

AF:

0.0723

AC:

3602

AN:

49832

Middle Eastern (MID)

AF:

0.0469

AC:

210

AN:

4482

European-Non Finnish (NFE)

AF:

0.0211

AC:

20462

AN:

971290

Other (OTH)

AF:

0.0384

AC:

2067

AN:

53886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2182

4365

6547

8730

10912

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

956

1912

2868

3824

4780

<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

AF:

0.0577

AC:

5016

AN:

86988

Hom.:

236

Cov.:

AF XY:

0.0655

AC XY:

2791

AN XY:

42634

show subpopulations

African (AFR)

AF:

0.0118

AC:

288

AN:

24358

American (AMR)

AF:

0.0915

AC:

751

AN:

8206

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

1932

East Asian (EAS)

AF:

0.286

AC:

1185

AN:

4150

South Asian (SAS)

AF:

0.101

AC:

414

AN:

4098

European-Finnish (FIN)

AF:

0.151

AC:

811

AN:

5358

Middle Eastern (MID)

AF:

0.0920

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.0375

AC:

1386

AN:

36986

Other (OTH)

AF:

0.0522

AC:

AN:

1168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

231

462

693

924

1155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000373

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Parkinson disease 11, autosomal dominant, susceptibility to

Benign:2

Apr 22, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 26, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 23.92% East Asian, with 176 homozygotes (VQSRTrancheINDEL99.00to99.50)

not provided

Benign:1

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.044

Mutation Taster

=196/4

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over