rs3213232

Positions:

• chr11-2133734-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000612.6(IGF2):​c.158-69C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0844 in 1,579,410 control chromosomes in the GnomAD database, including 7,237 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1787 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5450 hom.)
• Consequence: IGF2 NM_000612.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.64

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2	NM_000612.6	c.158-69C>T		intron_variant		ENST00000416167.7	NP_000603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2	ENST00000416167.7	c.158-69C>T		intron_variant		1	NM_000612.6	ENSP00000414497.2
IGF2	ENST00000381392.5	c.158-60C>T		intron_variant		1		ENSP00000370799.1
IGF2	ENST00000381406.8	c.158-60C>T		intron_variant		2		ENSP00000370813.4
ENSG00000284779	ENST00000643349.2	c.*210-69C>T		intron_variant				ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18936 AN: 152110 Hom.: 1781 Cov.: 33

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0416

Gnomad FIN AF: 0.0795

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0775

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.0801 AC: 114303 AN: 1427182 Hom.: 5450 AF XY: 0.0787 AC XY: 55808 AN XY: 708846

Gnomad4 AFR exome AF: 0.254

Gnomad4 AMR exome AF: 0.0599

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.000342

Gnomad4 SAS exome AF: 0.0467

Gnomad4 FIN exome AF: 0.0795

Gnomad4 NFE exome AF: 0.0803

Gnomad4 OTH exome AF: 0.0835

GnomAD4 genome AF: 0.124 AC: 18943 AN: 152228 Hom.: 1787 Cov.: 33 AF XY: 0.122 AC XY: 9053 AN XY: 74458

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.0937

Gnomad4 ASJ AF: 0.0968

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0414

Gnomad4 FIN AF: 0.0795

Gnomad4 NFE AF: 0.0775

Gnomad4 OTH AF: 0.127

Alfa AF: 0.0911 Hom.: 637

Bravo AF: 0.135

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.41
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3213232; hg19: chr11-2154964; COSMIC: COSV56098177; COSMIC: COSV56098177;