chr11-2133091-C-G

Position:

chr11-2133091-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000612.6(IGF2):c.439G>C(p.Glu147Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,607,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

IGF2
NM_000612.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.0750

Variant links:

Genes affected

IGF2 (HGNC:5466): (insulin like growth factor 2) This gene encodes a member of the insulin family of polypeptide growth factors, which are involved in development and growth. It is an imprinted gene, expressed only from the paternal allele, and epigenetic changes at this locus are associated with Wilms tumour, Beckwith-Wiedemann syndrome, rhabdomyosarcoma, and Silver-Russell syndrome. A read-through INS-IGF2 gene exists, whose 5' region overlaps the INS gene and the 3' region overlaps this gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

IGF2 links:

ENSG00000284779 (HGNC:):

ENSG00000284779 links:

INS-IGF2 (HGNC:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

INS-IGF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07359061).

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2	NM_000612.6 linkuse as main transcript	c.439G>C	p.Glu147Gln	missense_variant	4/4	ENST00000416167.7	NP_000603.1	P01344-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IGF2	ENST00000416167.7 linkuse as main transcript	c.439G>C	p.Glu147Gln	missense_variant	4/4	1	NM_000612.6	ENSP00000414497.2	P01344-1
IGF2	ENST00000381392.5 linkuse as main transcript	c.448G>C	p.Glu150Gln	missense_variant	4/4	1		ENSP00000370799.1	P01344-2
IGF2	ENST00000381406.8 linkuse as main transcript	c.448G>C	p.Glu150Gln	missense_variant	4/4	2		ENSP00000370813.4	P01344-2
ENSG00000284779	ENST00000643349.2 linkuse as main transcript	c.*491G>C		3_prime_UTR_variant	5/5			ENSP00000495715.1	A0A2R8Y747

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000696

AC:

AN:

244266

Hom.:

AF XY:

0.0000828

AC XY:

AN XY:

132810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000592

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000148

AC:

215

AN:

1455730

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

723564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000455

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.000118

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 14, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 147 of the IGF2 protein (p.Glu147Gln). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 2178673). This variant has not been reported in the literature in individuals affected with IGF2-related conditions. This variant is present in population databases (rs150866176, gnomAD 0.01%). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.66

CADD

Benign

3.7

DANN

Benign

0.51

DEOGEN2

Benign

0.23

T;.;T;T;.;.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.62

.;.;.;.;T;T;.;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.074

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;.;L;L;.;.;L;L

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.44

N;N;N;.;N;N;N;N

REVEL

Benign

0.097

Sift

Benign

0.37

T;T;T;.;T;T;T;T

Sift4G

Benign

0.53

T;T;T;.;T;T;T;T

Polyphen

0.80

P;.;P;P;.;.;P;P

Vest4

0.056

MVP

0.32

MPC

0.73

ClinPred

0.041

GERP RS

-1.6

Varity_R

0.052

gMVP

0.30

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