Genetic Variant IGF2:p.Gly169Arg (chr11-2133025-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000612.6(IGF2):c.505G>C(p.Gly169Arg) 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G169W) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

IGF2
NM_000612.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.579

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24639052).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000612.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGF2	NM_000612.6	MANE Select	c.505G>C	p.Gly169Arg	missense	Exon 4 of 4	NP_000603.1	P01344-1
IGF2	NM_001127598.3		c.673G>C	p.Gly225Arg	missense	Exon 5 of 5	NP_001121070.1	P01344-3
IGF2	NM_001007139.6		c.505G>C	p.Gly169Arg	missense	Exon 5 of 5	NP_001007140.2	P01344-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGF2	ENST00000416167.7	TSL:1 MANE Select	c.505G>C	p.Gly169Arg	missense	Exon 4 of 4	ENSP00000414497.2	P01344-1
IGF2	ENST00000434045.6	TSL:1	c.673G>C	p.Gly225Arg	missense	Exon 5 of 5	ENSP00000391826.2	P01344-3
IGF2	ENST00000381392.5	TSL:1	c.514G>C	p.Gly172Arg	missense	Exon 4 of 4	ENSP00000370799.1	P01344-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.00094

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.25

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.1

PhyloP100

0.58

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.29

Sift

Benign

0.067

Sift4G

Benign

0.10

Polyphen

0.89

Vest4

0.24

MutPred

0.11

Loss of catalytic residue at D165 (P = 0.1224)

MVP

0.92

MPC

1.8

ClinPred

0.76

GERP RS

2.1

Varity_R

0.078

gMVP

0.48

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over