2-232756197-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr2-232756197-C-CTTTTTTTT
• rs759525243
• NM_001103146.3:c.268-13_268-6dupTTTTTTTT

Variant summary

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

The NM_001103146.3(GIGYF2):​c.268-13_268-6dupTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), 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 0.00037 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00087 (4 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.268-13_268-6dupTTTTTTTT		splice_region intron	N/A	NP_001096616.1	Q6Y7W6-1
	GIGYF2	NM_001103147.2		c.268-13_268-6dupTTTTTTTT		splice_region intron	N/A	NP_001096617.1	Q6Y7W6-3
	GIGYF2	NM_015575.4		c.268-13_268-6dupTTTTTTTT		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_268-25insTTTTTTTT		intron	N/A	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.268-26_268-25insTTTTTTTT		intron	N/A	ENSP00000387170.3	Q6Y7W6-3
	GIGYF2	ENST00000409547.5	TSL:1	c.268-26_268-25insTTTTTTTT		intron	N/A	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes AF: 0.000370 AC: 38 AN: 102696 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000231

Gnomad AMI AF: 0.00137

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000266

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000816

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000868 AC: 527 AN: 607462 Hom.: 4 Cov.: 0 AF XY: 0.000919 AC XY: 296 AN XY: 322126

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

African (AFR) AF: 0.00128 AC: 19 AN: 14862

American (AMR) AF: 0.00136 AC: 35 AN: 25762

Ashkenazi Jewish (ASJ) AF: 0.000996 AC: 16 AN: 16062

East Asian (EAS) AF: 0.000955 AC: 30 AN: 31420

South Asian (SAS) AF: 0.00183 AC: 88 AN: 48210

European-Finnish (FIN) AF: 0.000270 AC: 10 AN: 36996

Middle Eastern (MID) AF: 0.00133 AC: 3 AN: 2264

European-Non Finnish (NFE) AF: 0.000756 AC: 304 AN: 402164

Other (OTH) AF: 0.000740 AC: 22 AN: 29722

⚠️ 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.

GnomAD4 genome AF: 0.000370 AC: 38 AN: 102662 Hom.: 0 Cov.: 0 AF XY: 0.000442 AC XY: 21 AN XY: 47562

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

African (AFR) AF: 0.000230 AC: 6 AN: 26036

American (AMR) AF: 0.00 AC: 0 AN: 8740

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

East Asian (EAS) AF: 0.000267 AC: 1 AN: 3746

South Asian (SAS) AF: 0.00 AC: 0 AN: 2896

European-Finnish (FIN) AF: 0.000816 AC: 3 AN: 3676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 152

European-Non Finnish (NFE) AF: 0.000514 AC: 27 AN: 52562

Other (OTH) AF: 0.00 AC: 0 AN: 1330

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000255351), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00793 Hom.: 144

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;