11-2133057-AG-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_000612.6(IGF2):c.472del(p.Leu158Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000661 in 1,602,948 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (1 hom.)
• Consequence: IGF2 NM_000612.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.22

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 0 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 0.131 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2	NM_000612.6	c.472del	p.Leu158Ter	frameshift_variant	4/4	ENST00000416167.7
INS-IGF2	NR_003512.4	n.1186del		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2	ENST00000416167.7	c.472del	p.Leu158Ter	frameshift_variant	4/4	1	NM_000612.6	P4
	ENST00000643349.2	c.*524del		3_prime_UTR_variant	5/5			P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000202 AC: 49 AN: 242378 Hom.: 1 AF XY: 0.000197 AC XY: 26 AN XY: 131736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000433

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000689 AC: 100 AN: 1450752 Hom.: 1 Cov.: 31 AF XY: 0.0000569 AC XY: 41 AN XY: 720444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000762

Gnomad4 NFE exome AF: 0.0000769

Gnomad4 OTH exome AF: 0.000184

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000756

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	Jul 25, 2023	ClinVar contains an entry for this variant (Variation ID: 504012). 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. This variant has not been reported in the literature in individuals affected with IGF2-related conditions. This variant is present in population databases (rs748459239, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change creates a premature translational stop signal (p.Leu158*) in the IGF2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the IGF2 protein. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2017	The c.472delC variant in the IGF2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.472delC variant causes a frameshift, changing codon Leucine 158 to a premature Stop codon, denoted p.L158Ter. This variant is predicted to cause loss of normal protein function through protein truncation. However, the c.472delC variant is observed in 44/106950 (0.04%) alleles from individuals of non-Finnish European background, including one homozygous individual, in large population cohorts (Lek et al., 2016). We interpret c.472delC as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs748459239; hg19: chr11-2154287;