2-232756197-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr2-232756197-C-CTTTTTTTTTTTTTTTTTT
• rs759525243
• NM_001103146.3:c.268-23_268-6dupTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_001103146.3(GIGYF2):​c.268-23_268-6dupTTTTTTTTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), 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 0.0000097 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GIGYF2 NM_001103146.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.876
• Publications: 0 publications found

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

ACMG classification

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	NM_001103146.3	MANE Select	c.268-23_268-6dupTTTTTTTTTTTTTTTTTT		splice_region intron	N/A	NP_001096616.1	Q6Y7W6-1
	GIGYF2	NM_001103147.2		c.268-23_268-6dupTTTTTTTTTTTTTTTTTT		splice_region intron	N/A	NP_001096617.1	Q6Y7W6-3
	GIGYF2	NM_015575.4		c.268-23_268-6dupTTTTTTTTTTTTTTTTTT		splice_region intron	N/A	NP_056390.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.268-26_268-25insTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.268-26_268-25insTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000387170.3	Q6Y7W6-3
	GIGYF2	ENST00000409547.5	TSL:1	c.268-26_268-25insTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes AF: 0.00000974 AC: 1 AN: 102712 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 9 AN: 607960 Hom.: 0 Cov.: 0 AF XY: 0.0000124 AC XY: 4 AN XY: 322394

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

African (AFR) AF: 0.00 AC: 0 AN: 14868

American (AMR) AF: 0.00 AC: 0 AN: 25780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16078

East Asian (EAS) AF: 0.00 AC: 0 AN: 31438

South Asian (SAS) AF: 0.0000414 AC: 2 AN: 48302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37014

Middle Eastern (MID) AF: 0.000441 AC: 1 AN: 2268

European-Non Finnish (NFE) AF: 0.0000149 AC: 6 AN: 402474

Other (OTH) AF: 0.00 AC: 0 AN: 29738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000376977), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000974 AC: 1 AN: 102712 Hom.: 0 Cov.: 0 AF XY: 0.0000210 AC XY: 1 AN XY: 47572

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

African (AFR) AF: 0.0000384 AC: 1 AN: 26026

American (AMR) AF: 0.00 AC: 0 AN: 8736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2792

East Asian (EAS) AF: 0.00 AC: 0 AN: 3762

South Asian (SAS) AF: 0.00 AC: 0 AN: 2920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 172

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52578

Other (OTH) AF: 0.00 AC: 0 AN: 1318

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88

Splicing

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

Other links and lift over

dbSNP: rs759525243; hg19: chr2-233620907;