rs2239681

Variant names:

• chr11-2146751-G-A
• rs2239681
• ENST00000397270.1:c.*47-6C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2146751-G-A
• chr11-2146751-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000397270.1(INS-IGF2):​c.*47-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 254,874 control chromosomes in the GnomAD database, including 12,393 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (5368 hom., cov: 33)
  • Exomes 𝑓: 0.35 (7025 hom.)
• Consequence: INS-IGF2 ENST00000397270.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.745
• Publications: 19 publications found

Genes affected

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]

ENSG00000284779 (HGNC:):

IGF2-AS (HGNC:14062): (IGF2 antisense RNA) This gene is expressed in antisense to the insulin-like growth factor 2 (IGF2) gene and is imprinted and paternally expressed. It is thought to be non-coding because the putative protein is not conserved and translation is predicted to trigger nonsense mediated decay (NMD). Transcripts from this gene are produced in tumors and may function to suppress cell growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

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]

IGF2 Gene-Disease associations (from GenCC):

• Silver-Russell syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.*47-6C>T		splice_region_variant, intron_variant	Intron 4 of 4		NP_001035835.1
IGF2	NM_001007139.6	c.-7+815C>T		intron_variant	Intron 2 of 4		NP_001007140.2
INS-IGF2	NR_003512.4	n.708+815C>T		intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.*47-6C>T		splice_region_variant, intron_variant	Intron 4 of 4	1		ENSP00000380440.1
ENSG00000284779	ENST00000643349.2	c.*46+815C>T		intron_variant	Intron 2 of 4			ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39157 AN: 152004 Hom.: 5370 Cov.: 33

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.292

GnomAD4 exome AF: 0.348 AC: 35739 AN: 102752 Hom.: 7025 Cov.: 0 AF XY: 0.367 AC XY: 20413 AN XY: 55552

African (AFR) AF: 0.209 AC: 667 AN: 3190

American (AMR) AF: 0.254 AC: 1051 AN: 4138

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 786 AN: 2316

East Asian (EAS) AF: 0.632 AC: 2347 AN: 3716

South Asian (SAS) AF: 0.506 AC: 10214 AN: 20170

European-Finnish (FIN) AF: 0.280 AC: 1274 AN: 4556

Middle Eastern (MID) AF: 0.473 AC: 192 AN: 406

European-Non Finnish (NFE) AF: 0.298 AC: 17603 AN: 59048

Other (OTH) AF: 0.308 AC: 1605 AN: 5212

GnomAD4 genome AF: 0.257 AC: 39149 AN: 152122 Hom.: 5368 Cov.: 33 AF XY: 0.262 AC XY: 19496 AN XY: 74362

African (AFR) AF: 0.201 AC: 8327 AN: 41516

American (AMR) AF: 0.226 AC: 3452 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1030 AN: 3470

East Asian (EAS) AF: 0.530 AC: 2735 AN: 5164

South Asian (SAS) AF: 0.463 AC: 2232 AN: 4824

European-Finnish (FIN) AF: 0.243 AC: 2571 AN: 10590

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 17997 AN: 67948

Other (OTH) AF: 0.290 AC: 612 AN: 2108

Alfa AF: 0.266 Hom.: 8678

Bravo AF: 0.253

Asia WGS AF: 0.442 AC: 1536 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.27
DANN	Benign	0.67
PhyloP100		-0.74
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2239681; hg19: chr11-2167981;