11-2133034-G-T

Variant names:

• chr11-2133034-G-T
• NM_000612.6:c.496C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000612.6(IGF2):​c.496C>A​(p.Pro166Thr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF2 NM_000612.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.78

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]

ENSG00000284779 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2	NM_000612.6	c.496C>A	p.Pro166Thr	missense_variant	Exon 4 of 4	ENST00000416167.7	NP_000603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2	ENST00000416167.7	c.496C>A	p.Pro166Thr	missense_variant	Exon 4 of 4	1	NM_000612.6	ENSP00000414497.2
IGF2	ENST00000381392.5	c.505C>A	p.Pro169Thr	missense_variant	Exon 4 of 4	1		ENSP00000370799.1
IGF2	ENST00000381406.8	c.505C>A	p.Pro169Thr	missense_variant	Exon 4 of 4	2		ENSP00000370813.4
ENSG00000284779	ENST00000643349	c.*503C>A		3_prime_UTR_variant	Exon 5 of 5			ENSP00000495715.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

IGF2-related disorder Uncertain:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IGF2 c.496C>A variant is predicted to result in the amino acid substitution p.Pro166Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;D;D;.;.;D;D
Eigen	Benign	0.18
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.67	.;.;.;.;T;T;.;T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.0	M;.;M;M;.;.;M;M
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.2	D;D;D;.;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;.;D;D;D;D
Polyphen		0.99	D;.;D;D;.;.;D;D
Vest4		0.40
MutPred		0.74		Gain of phosphorylation at P166 (P = 0.0218);.;Gain of phosphorylation at P166 (P = 0.0218);Gain of phosphorylation at P166 (P = 0.0218);.;.;Gain of phosphorylation at P166 (P = 0.0218);Gain of phosphorylation at P166 (P = 0.0218);
MVP		0.88
MPC		1.8
ClinPred		0.98	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.52
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2154264;