3-185824915-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006548.6(IGF2BP2):c.46G>A(p.Ala16Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000057 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGF2BP2 NM_006548.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.282

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 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=0.16125995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2BP2	NM_006548.6	c.46G>A	p.Ala16Thr	missense_variant	1/16	ENST00000382199.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2BP2	ENST00000382199.7	c.46G>A	p.Ala16Thr	missense_variant	1/16	1	NM_006548.6	P1
IGF2BP2	ENST00000346192.7	c.46G>A	p.Ala16Thr	missense_variant	1/15	1
IGF2BP2	ENST00000457616.6	c.46G>A	p.Ala16Thr	missense_variant	1/16	5
IGF2BP2	ENST00000466476.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000565 AC: 8 AN: 1415676 Hom.: 0 Cov.: 31 AF XY: 0.00000426 AC XY: 3 AN XY: 703502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000148

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000828 AC: 1

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

Dec 08, 2021

The c.46G>A (p.A16T) alteration is located in exon 1 (coding exon 1) of the IGF2BP2 gene. This alteration results from a G to A substitution at nucleotide position 46, causing the alanine (A) at amino acid position 16 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.092	T;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N;.;N
MutationTaster	Benign	0.60	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.073
Sift	Benign	0.068	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.87	P;B;P
Vest4		0.13
MutPred		0.48		Gain of glycosylation at T15 (P = 0.0396);Gain of glycosylation at T15 (P = 0.0396);Gain of glycosylation at T15 (P = 0.0396);
MVP		0.31
MPC		0.94
ClinPred		0.22	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.35

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: rs764179905; hg19: chr3-185542703;