11-2133011-TG-TGG

Variant names:

• chr11-2133011-T-TG
• rs755455183
• NM_000612.6:c.518dupC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_000612.6(IGF2):​c.518dupC​(p.Glu174ArgfsTer50) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,394,094 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P173P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: IGF2 NM_000612.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.11
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.046 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2	NM_000612.6	MANE Select	c.518dupC	p.Glu174ArgfsTer50	frameshift	Exon 4 of 4	NP_000603.1	P01344-1
	IGF2	NM_001127598.3		c.686dupC	p.Glu230ArgfsTer50	frameshift	Exon 5 of 5	NP_001121070.1	P01344-3
	IGF2	NM_001007139.6		c.518dupC	p.Glu174ArgfsTer50	frameshift	Exon 5 of 5	NP_001007140.2	P01344-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2	ENST00000416167.7	TSL:1 MANE Select	c.518dupC	p.Glu174ArgfsTer50	frameshift	Exon 4 of 4	ENSP00000414497.2	P01344-1
	IGF2	ENST00000434045.6	TSL:1	c.686dupC	p.Glu230ArgfsTer50	frameshift	Exon 5 of 5	ENSP00000391826.2	P01344-3
	IGF2	ENST00000381392.5	TSL:1	c.527dupC	p.Glu177ArgfsTer50	frameshift	Exon 4 of 4	ENSP00000370799.1	P01344-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000118 AC: 23 AN: 194502 AF XY: 0.0000943

Gnomad AFR exome AF: 0.000289

Gnomad AMR exome AF: 0.0000417

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000675

Gnomad FIN exome AF: 0.0000517

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.000440

GnomAD4 exome AF: 0.0000201 AC: 28 AN: 1394094 Hom.: 0 Cov.: 31 AF XY: 0.0000218 AC XY: 15 AN XY: 687102

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000129 AC: 4 AN: 30902

American (AMR) AF: 0.0000588 AC: 2 AN: 34016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22714

East Asian (EAS) AF: 0.0000534 AC: 2 AN: 37420

South Asian (SAS) AF: 0.00 AC: 0 AN: 77332

European-Finnish (FIN) AF: 0.000158 AC: 8 AN: 50760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5454

European-Non Finnish (NFE) AF: 0.00000927 AC: 10 AN: 1078242

Other (OTH) AF: 0.0000349 AC: 2 AN: 57254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

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

Other links and lift over

dbSNP: rs755455183; hg19: chr11-2154241; COSMIC: COSV56097951; COSMIC: COSV56097951;