Genetic Variant GIGYF2:c.171+103C>A (chr2-232747847-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001103146.3(GIGYF2):c.171+103C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000106 in 943,640 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.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

GIGYF2
NM_001103146.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.27

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: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

GIGYF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

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	Effect	Exon Rank	Protein	UniProt
GIGYF2	NM_001103146.3	MANE Select	c.171+103C>A	intron	N/A	NP_001096616.1	Q6Y7W6-1
GIGYF2	NM_001103147.2		c.171+103C>A	intron	N/A	NP_001096617.1	Q6Y7W6-3
GIGYF2	NM_015575.4		c.171+103C>A	intron	N/A	NP_056390.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.171+103C>A	intron	N/A	ENSP00000362664.5	Q6Y7W6-1
GIGYF2	ENST00000409451.7	TSL:1	c.171+103C>A	intron	N/A	ENSP00000387170.3	Q6Y7W6-3
GIGYF2	ENST00000409547.5	TSL:1	c.171+103C>A	intron	N/A	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000106

AC:

AN:

943640

Hom.:

AF XY:

0.00000205

AC XY:

AN XY:

487276

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

23300

American (AMR)

AF:

0.00

AC:

AN:

39628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22354

East Asian (EAS)

AF:

0.00

AC:

AN:

35348

South Asian (SAS)

AF:

0.00

AC:

AN:

72398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3162

European-Non Finnish (NFE)

AF:

0.00000150

AC:

AN:

665564

Other (OTH)

AF:

0.00

AC:

AN:

43456

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.31

(source)

DANN

Benign

0.76

PhyloP100

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over