11-2133011-T-TG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

The NM_000612.6(IGF2):​c.518dupC​(p.Glu174fs) 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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.11
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. 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 0 pathogenic variants in the truncated region.
BS2
High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IGF2NM_000612.6 linkuse as main transcriptc.518dupC p.Glu174fs frameshift_variant 4/4 ENST00000416167.7 NP_000603.1 P01344-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IGF2ENST00000416167.7 linkuse as main transcriptc.518dupC p.Glu174fs frameshift_variant 4/41 NM_000612.6 ENSP00000414497.2 P01344-1
IGF2ENST00000381392.5 linkuse as main transcriptc.527dupC p.Glu177fs frameshift_variant 4/41 ENSP00000370799.1 P01344-2
IGF2ENST00000381406.8 linkuse as main transcriptc.527dupC p.Glu177fs frameshift_variant 4/42 ENSP00000370813.4 P01344-2
ENSG00000284779ENST00000643349.2 linkuse as main transcriptc.*570dupC 3_prime_UTR_variant 5/5 ENSP00000495715.1 A0A2R8Y747

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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 28, 2023This 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 submitterclinical testingGeneDxMar 26, 2021Not 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

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755455183; hg19: chr11-2154241; API