11-2148634-T-C

Variant names:

• chr11-2148634-T-C
• rs3741206
• ENST00000397270.1:c.407+492A>G

Variant summary

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

The ENST00000397270.1(INS-IGF2):​c.407+492A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 162,972 control chromosomes in the GnomAD database, including 10,480 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 0.35 (9595 hom., cov: 32)
  • Exomes 𝑓: 0.37 (885 hom.)
• Consequence: INS-IGF2 ENST00000397270.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397270.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2-AS	NR_028043.2		n.2036T>C		non_coding_transcript_exon	Exon 3 of 3
	IGF2-AS	NR_133657.1		n.1925T>C		non_coding_transcript_exon	Exon 3 of 3
	INS-IGF2	NM_001042376.3		c.407+492A>G		intron	N/A	NP_001035835.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS-IGF2	ENST00000397270.1	TSL:1	c.407+492A>G		intron	N/A	ENSP00000380440.1
	ENSG00000284779	ENST00000643349.2		c.254+492A>G		intron	N/A	ENSP00000495715.1
	IGF2-AS	ENST00000381361.4	TSL:2	n.2031T>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52884 AN: 151836 Hom.: 9563 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.349

GnomAD4 exome AF: 0.372 AC: 4098 AN: 11016 Hom.: 885 Cov.: 0 AF XY: 0.361 AC XY: 2009 AN XY: 5562

African (AFR) AF: 0.333 AC: 66 AN: 198

American (AMR) AF: 0.476 AC: 804 AN: 1690

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 58 AN: 182

East Asian (EAS) AF: 0.205 AC: 90 AN: 440

South Asian (SAS) AF: 0.231 AC: 195 AN: 844

European-Finnish (FIN) AF: 0.450 AC: 109 AN: 242

Middle Eastern (MID) AF: 0.0833 AC: 2 AN: 24

European-Non Finnish (NFE) AF: 0.375 AC: 2565 AN: 6838

Other (OTH) AF: 0.375 AC: 209 AN: 558

GnomAD4 genome AF: 0.349 AC: 52967 AN: 151956 Hom.: 9595 Cov.: 32 AF XY: 0.351 AC XY: 26074 AN XY: 74244

African (AFR) AF: 0.294 AC: 12196 AN: 41422

American (AMR) AF: 0.476 AC: 7269 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1235 AN: 3468

East Asian (EAS) AF: 0.190 AC: 980 AN: 5156

South Asian (SAS) AF: 0.269 AC: 1296 AN: 4820

European-Finnish (FIN) AF: 0.413 AC: 4362 AN: 10558

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24392 AN: 67950

Other (OTH) AF: 0.349 AC: 735 AN: 2106

Alfa AF: 0.352 Hom.: 24070

Bravo AF: 0.352

Asia WGS AF: 0.237 AC: 822 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.0
DANN	Benign	0.73
PhyloP100		0.055
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3741206; hg19: chr11-2169864;