3-185675828-T-C

Position:

• chr3-185675828-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006548.6(IGF2BP2):​c.898A>G​(p.Ile300Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: IGF2BP2 NM_006548.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26111132).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2BP2	NM_006548.6	c.898A>G	p.Ile300Val	missense_variant	8/16	ENST00000382199.7	NP_006539.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2BP2	ENST00000382199.7	c.898A>G	p.Ile300Val	missense_variant	8/16	1	NM_006548.6	ENSP00000371634.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461402 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2024

The c.898A>G (p.I300V) alteration is located in exon 8 (coding exon 8) of the IGF2BP2 gene. This alteration results from a A to G substitution at nucleotide position 898, causing the isoleucine (I) at amino acid position 300 to be replaced by a valine (V). 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	0.21
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.;.
Eigen	Benign	0.012
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L;.;L;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.61	N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.22	T;T;T;.
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.090	B;B;B;B
Vest4		0.44
MutPred		0.66		.;Gain of loop (P = 0.0312);.;.;
MVP		0.53
MPC		1.2
ClinPred		0.72	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.79

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

Other links and lift over

dbSNP: rs1719254605; hg19: chr3-185393616;