rs2305137

Variant names:

• chr2-232847339-G-A
• rs2305137
• NM_001103146.3:c.3461-9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001103146.3(GIGYF2):​c.3461-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,606,238 control chromosomes in the GnomAD database, including 330,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32610 hom., cov: 32)
  • Exomes 𝑓: 0.64 (298297 hom.)
• Consequence: GIGYF2 NM_001103146.3 intron
• Scores: Splicing: ADA: 0.0003926
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.901
• Publications: 14 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: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-232847339-G-A is Benign according to our data. Variant chr2-232847339-G-A is described in ClinVar as Benign. ClinVar VariationId is 518337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.685 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	NM_001103146.3	MANE Select	c.3461-9G>A		intron	N/A	NP_001096616.1	Q6Y7W6-1
	GIGYF2	NM_001103147.2		c.3524-9G>A		intron	N/A	NP_001096617.1	Q6Y7W6-3
	GIGYF2	NM_015575.4		c.3461-9G>A		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.3461-9G>A		intron	N/A	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.3524-9G>A		intron	N/A	ENSP00000387170.3	Q6Y7W6-3
	GIGYF2	ENST00000409547.5	TSL:1	c.3461-9G>A		intron	N/A	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99004 AN: 151850 Hom.: 32585 Cov.: 32

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.667

GnomAD2 exomes AF: 0.642 AC: 161496 AN: 251378 AF XY: 0.626

Gnomad AFR exome AF: 0.624

Gnomad AMR exome AF: 0.742

Gnomad ASJ exome AF: 0.664

Gnomad EAS exome AF: 0.673

Gnomad FIN exome AF: 0.766

Gnomad NFE exome AF: 0.660

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.635 AC: 923521 AN: 1454270 Hom.: 298297 Cov.: 34 AF XY: 0.627 AC XY: 454117 AN XY: 723992

African (AFR) AF: 0.622 AC: 20735 AN: 33314

American (AMR) AF: 0.737 AC: 32966 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 17432 AN: 26070

East Asian (EAS) AF: 0.709 AC: 28120 AN: 39662

South Asian (SAS) AF: 0.371 AC: 31960 AN: 86100

European-Finnish (FIN) AF: 0.764 AC: 40827 AN: 53414

Middle Eastern (MID) AF: 0.568 AC: 2868 AN: 5046

European-Non Finnish (NFE) AF: 0.643 AC: 710995 AN: 1105898

Other (OTH) AF: 0.626 AC: 37618 AN: 60058

GnomAD4 genome AF: 0.652 AC: 99082 AN: 151968 Hom.: 32610 Cov.: 32 AF XY: 0.654 AC XY: 48558 AN XY: 74272

African (AFR) AF: 0.626 AC: 25917 AN: 41406

American (AMR) AF: 0.696 AC: 10627 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 2309 AN: 3472

East Asian (EAS) AF: 0.668 AC: 3455 AN: 5170

South Asian (SAS) AF: 0.376 AC: 1812 AN: 4814

European-Finnish (FIN) AF: 0.768 AC: 8109 AN: 10564

Middle Eastern (MID) AF: 0.640 AC: 187 AN: 292

European-Non Finnish (NFE) AF: 0.658 AC: 44696 AN: 67962

Other (OTH) AF: 0.659 AC: 1394 AN: 2116

Alfa AF: 0.661 Hom.: 19073

Bravo AF: 0.656

Asia WGS AF: 0.498 AC: 1733 AN: 3478

EpiCase AF: 0.651

EpiControl AF: 0.656

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Parkinson disease 11, autosomal dominant, susceptibility to (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.034
DANN	Benign	0.40
PhyloP100		-0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.0020
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2305137;

hg19: chr2-233712049;