2-232735194-A-C

Variant names:

• chr2-232735194-A-C
• rs11555646
• NM_001103146.3:c.-4A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001103146.3(GIGYF2):​c.-4A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,591,010 control chromosomes in the GnomAD database, including 105,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7997 hom., cov: 32)
  • Exomes 𝑓: 0.36 (97822 hom.)
• Consequence: GIGYF2 NM_001103146.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.72
• Publications: 22 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 2-232735194-A-C is Benign according to our data. Variant chr2-232735194-A-C is described in ClinVar as [Benign]. Clinvar id is 1246966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.-4A>C		5_prime_UTR_variant	Exon 3 of 29	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.-4A>C		5_prime_UTR_variant	Exon 3 of 29	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48158 AN: 152008 Hom.: 7988 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.349 AC: 87432 AN: 250634 AF XY: 0.367

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.358 AC: 515414 AN: 1438884 Hom.: 97822 Cov.: 27 AF XY: 0.367 AC XY: 263075 AN XY: 717100

African (AFR) AF: 0.267 AC: 8837 AN: 33108

American (AMR) AF: 0.256 AC: 11428 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8613 AN: 25992

East Asian (EAS) AF: 0.291 AC: 11525 AN: 39592

South Asian (SAS) AF: 0.628 AC: 53775 AN: 85614

European-Finnish (FIN) AF: 0.239 AC: 12765 AN: 53372

Middle Eastern (MID) AF: 0.431 AC: 2467 AN: 5718

European-Non Finnish (NFE) AF: 0.352 AC: 384433 AN: 1091252

Other (OTH) AF: 0.362 AC: 21571 AN: 59584

GnomAD4 genome AF: 0.317 AC: 48182 AN: 152126 Hom.: 7997 Cov.: 32 AF XY: 0.316 AC XY: 23515 AN XY: 74386

African (AFR) AF: 0.266 AC: 11045 AN: 41504

American (AMR) AF: 0.291 AC: 4447 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1168 AN: 3470

East Asian (EAS) AF: 0.333 AC: 1726 AN: 5184

South Asian (SAS) AF: 0.623 AC: 3006 AN: 4824

European-Finnish (FIN) AF: 0.237 AC: 2508 AN: 10582

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.341 AC: 23172 AN: 67966

Other (OTH) AF: 0.318 AC: 672 AN: 2112

Alfa AF: 0.330 Hom.: 15210

Bravo AF: 0.309

Asia WGS AF: 0.494 AC: 1716 AN: 3478

EpiCase AF: 0.347

EpiControl AF: 0.344

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 22, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11555646; hg19: chr2-233599904; COSMIC: COSV65247676; COSMIC: COSV65247676;