11-2133011-T-TG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_000612.6(IGF2):c.518_519insC(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. Variant has been reported in ClinVar as Uncertain significance (★★).

• 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

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2	NM_000612.6	c.518_519insC	p.Glu174ArgfsTer50	frameshift_variant	4/4	ENST00000416167.7
INS-IGF2	NR_003512.4	n.1232_1233insC		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2	ENST00000416167.7	c.518_519insC	p.Glu174ArgfsTer50	frameshift_variant	4/4	1	NM_000612.6	P4
	ENST00000643349.2	c.*570_*571insC		3_prime_UTR_variant	5/5			P1

Frequencies

GnomAD3 genomes Cov.: 33

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

Gnomad4 AFR exome AF: 0.000129

Gnomad4 AMR exome AF: 0.0000588

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000534

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000158

Gnomad4 NFE exome AF: 0.00000927

Gnomad4 OTH exome AF: 0.0000349

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2023	This sequence change results in a frameshift in the IGF2 gene (p.Glu174Argfs*50). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the IGF2 protein and extend the protein by 42 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with IGF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 451532). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2021	Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein elongation as the last seven amino acids are replaced with 49 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs755455183; hg19: chr11-2154241;