Genetic Variant IGF2BP2:p.Arg597Leu (chr3-185645541-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006548.6(IGF2BP2):c.1790G>T(p.Arg597Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

IGF2BP2
NM_006548.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

Variant links:

Genes affected

IGF2BP2 (HGNC:28867): (insulin like growth factor 2 mRNA binding protein 2) This gene encodes a protein that binds the 5' UTR of insulin-like growth factor 2 (IGF2) mRNA and regulates its translation. It plays an important role in metabolism and variation in this gene is associated with susceptibility to diabetes. Alternative splicing and promoter usage results in multiple transcript variants. Related pseudogenes are found on several chromosomes. [provided by RefSeq, Sep 2016]

IGF2BP2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11583057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2BP2	NM_006548.6 link	c.1790G>T	p.Arg597Leu	missense_variant	Exon 16 of 16	ENST00000382199.7	NP_006539.3	Q9Y6M1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGF2BP2	ENST00000382199.7 link	c.1790G>T	p.Arg597Leu	missense_variant	Exon 16 of 16	1	NM_006548.6	ENSP00000371634.3	Q9Y6M1-2
IGF2BP2	ENST00000346192.7 link	c.1661G>T	p.Arg554Leu	missense_variant	Exon 15 of 15	1		ENSP00000320204.5	Q9Y6M1-1
IGF2BP2	ENST00000421047.3 link	c.1601G>T	p.Arg534Leu	missense_variant	Exon 15 of 15	1		ENSP00000413787.3	Q9Y6M1-3
IGF2BP2	ENST00000457616.6 link	c.1808G>T	p.Arg603Leu	missense_variant	Exon 16 of 16	5		ENSP00000410242.2	F8W930

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1790G>T (p.R597L) alteration is located in exon 16 (coding exon 16) of the IGF2BP2 gene. This alteration results from a G to T substitution at nucleotide position 1790, causing the arginine (R) at amino acid position 597 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T;.;.

Eigen

Benign

0.088

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

L;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.3

D;D;D;.

REVEL

Benign

0.071

Sift

Uncertain

0.0040

D;D;D;.

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.59

P;B;B;B

Vest4

0.19

MutPred

0.35

.;Gain of glycosylation at S604 (P = 0.0078);.;.;

MVP

0.15

MPC

1.0

ClinPred

0.95

GERP RS

4.5

Varity_R

0.26

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over