2-232794835-A-C

Variant names:

• chr2-232794835-A-C
• rs116074753
• NM_001103146.3:c.1370A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001103147.2(GIGYF2):​c.1433A>C​(p.Asn478Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,613,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: GIGYF2 NM_001103147.2 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -0.758
• Publications: 16 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06393552).
• BS2: High AC in GnomAd4 at 53 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103147.2. 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.1370A>C	p.Asn457Thr	missense	Exon 13 of 29	NP_001096616.1
	GIGYF2	NM_001103147.2		c.1433A>C	p.Asn478Thr	missense	Exon 15 of 31	NP_001096617.1
	GIGYF2	NM_015575.4		c.1370A>C	p.Asn457Thr	missense	Exon 15 of 31	NP_056390.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.1370A>C	p.Asn457Thr	missense	Exon 13 of 29	ENSP00000362664.5
	GIGYF2	ENST00000409451.7	TSL:1	c.1433A>C	p.Asn478Thr	missense	Exon 15 of 31	ENSP00000387170.3
	GIGYF2	ENST00000409547.5	TSL:1	c.1370A>C	p.Asn457Thr	missense	Exon 15 of 31	ENSP00000386537.1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000394 AC: 99 AN: 251254 AF XY: 0.000390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000757

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000478 AC: 698 AN: 1461608 Hom.: 1 Cov.: 31 AF XY: 0.000458 AC XY: 333 AN XY: 727150

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.000246 AC: 11 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000584 AC: 649 AN: 1111768

Other (OTH) AF: 0.000381 AC: 23 AN: 60388

GnomAD4 genome AF: 0.000349 AC: 53 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74320

African (AFR) AF: 0.000121 AC: 5 AN: 41476

American (AMR) AF: 0.000262 AC: 4 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 67978

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000598 Hom.: 1

Bravo AF: 0.000344

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Parkinson disease 11, autosomal dominant, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.7
DANN	Benign	0.87
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.76
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.026
Sift	Benign	0.32	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.26
MPC		0.33
ClinPred		0.012	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.022
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs116074753; hg19: chr2-233659545; COSMIC: COSV105300539; COSMIC: COSV105300539;