rs3213233

Positions:

• chr11-2133691-G-C

Variant summary

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

The NM_000612.6(IGF2):​c.158-26C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00516 in 1,611,764 control chromosomes in the GnomAD database, including 320 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 0.026 (165 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (155 hom.)
• Consequence: IGF2 NM_000612.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.438

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2	NM_000612.6	c.158-26C>G		intron_variant		ENST00000416167.7	NP_000603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2	ENST00000416167.7	c.158-26C>G		intron_variant		1	NM_000612.6	ENSP00000414497.2
IGF2	ENST00000381392.5	c.158-17C>G		intron_variant		1		ENSP00000370799.1
IGF2	ENST00000381406.8	c.158-17C>G		intron_variant		2		ENSP00000370813.4
ENSG00000284779	ENST00000643349.2	c.*210-26C>G		intron_variant				ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3971 AN: 152196 Hom.: 163 Cov.: 33

Gnomad AFR AF: 0.0890

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00716 AC: 1739 AN: 242754 Hom.: 71 AF XY: 0.00549 AC XY: 728 AN XY: 132682

Gnomad AFR exome AF: 0.0897

Gnomad AMR exome AF: 0.00554

Gnomad ASJ exome AF: 0.00854

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000428

Gnomad OTH exome AF: 0.00452

GnomAD4 exome AF: 0.00296 AC: 4324 AN: 1459450 Hom.: 155 Cov.: 31 AF XY: 0.00262 AC XY: 1901 AN XY: 726008

Gnomad4 AFR exome AF: 0.0910

Gnomad4 AMR exome AF: 0.00572

Gnomad4 ASJ exome AF: 0.00967

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000278

Gnomad4 OTH exome AF: 0.00700

GnomAD4 genome AF: 0.0262 AC: 3985 AN: 152314 Hom.: 165 Cov.: 33 AF XY: 0.0258 AC XY: 1918 AN XY: 74484

Gnomad4 AFR AF: 0.0891

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0138 Hom.: 13

Bravo AF: 0.0294

Asia WGS AF: 0.00606 AC: 22 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.4
DANN	Benign	0.50

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: rs3213233; hg19: chr11-2154921;