ENST00000397270.1:c.407+448A>G

Variant names:

• chr11-2148678-T-C
• rs3741204
• ENST00000397270.1:c.407+448A>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+448A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 177,588 control chromosomes in the GnomAD database, including 11,460 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 0.36 (9824 hom., cov: 31)
  • Exomes 𝑓: 0.33 (1636 hom.)
• Consequence: INS-IGF2 ENST00000397270.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.899
• Publications: 9 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 (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-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]

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 (AFR) allele frequency at 95% confidence interval = 0.381 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
	INS-IGF2	NM_001042376.3		c.407+448A>G		intron	N/A	NP_001035835.1
	IGF2	NM_001007139.6		c.-249+448A>G		intron	N/A	NP_001007140.2
	INS-IGF2	NR_003512.4		n.466+448A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS-IGF2	ENST00000397270.1	TSL:1	c.407+448A>G		intron	N/A	ENSP00000380440.1
	ENSG00000284779	ENST00000643349.2		c.254+448A>G		intron	N/A	ENSP00000495715.1
	IGF2	ENST00000481781.3	TSL:5	c.-249+448A>G		intron	N/A	ENSP00000511998.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54102 AN: 151636 Hom.: 9821 Cov.: 31

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.328

GnomAD4 exome AF: 0.331 AC: 8547 AN: 25834 Hom.: 1636 Cov.: 0 AF XY: 0.324 AC XY: 4246 AN XY: 13086

African (AFR) AF: 0.342 AC: 231 AN: 676

American (AMR) AF: 0.285 AC: 789 AN: 2772

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 206 AN: 646

East Asian (EAS) AF: 0.252 AC: 338 AN: 1342

South Asian (SAS) AF: 0.266 AC: 456 AN: 1712

European-Finnish (FIN) AF: 0.308 AC: 264 AN: 856

Middle Eastern (MID) AF: 0.250 AC: 24 AN: 96

European-Non Finnish (NFE) AF: 0.352 AC: 5751 AN: 16326

Other (OTH) AF: 0.347 AC: 488 AN: 1408

GnomAD4 genome AF: 0.357 AC: 54126 AN: 151754 Hom.: 9824 Cov.: 31 AF XY: 0.351 AC XY: 25997 AN XY: 74120

African (AFR) AF: 0.386 AC: 15940 AN: 41320

American (AMR) AF: 0.282 AC: 4299 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1151 AN: 3462

East Asian (EAS) AF: 0.279 AC: 1432 AN: 5124

South Asian (SAS) AF: 0.266 AC: 1279 AN: 4814

European-Finnish (FIN) AF: 0.339 AC: 3566 AN: 10516

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.372 AC: 25267 AN: 67940

Other (OTH) AF: 0.329 AC: 693 AN: 2108

Alfa AF: 0.174 Hom.: 310

Bravo AF: 0.354

Asia WGS AF: 0.313 AC: 1091 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	3.3
DANN	Benign	0.71
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs3741204; hg19: chr11-2169908;