ENST00000397270.1:c.407+472G>T

Variant names:

• chr11-2148654-C-A
• rs3741205
• ENST00000397270.1:c.407+472G>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.407+472G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 170,946 control chromosomes in the GnomAD database, including 42,630 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 0.70 (37911 hom., cov: 31)
  • Exomes 𝑓: 0.69 (4719 hom.)
• Consequence: INS-IGF2 ENST00000397270.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.869
• Publications: 20 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2-AS	NR_028043.2	n.2056C>A		non_coding_transcript_exon_variant	Exon 3 of 3
IGF2-AS	NR_133657.1	n.1945C>A		non_coding_transcript_exon_variant	Exon 3 of 3
INS-IGF2	NM_001042376.3	c.407+472G>T		intron_variant	Intron 3 of 4		NP_001035835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.407+472G>T		intron_variant	Intron 3 of 4	1		ENSP00000380440.1
ENSG00000284779	ENST00000643349.2	c.254+472G>T		intron_variant	Intron 1 of 4			ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106766 AN: 151708 Hom.: 37865 Cov.: 31

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.675

GnomAD4 exome AF: 0.689 AC: 13174 AN: 19120 Hom.: 4719 Cov.: 0 AF XY: 0.679 AC XY: 6492 AN XY: 9564

African (AFR) AF: 0.625 AC: 280 AN: 448

American (AMR) AF: 0.760 AC: 1860 AN: 2448

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 241 AN: 384

East Asian (EAS) AF: 0.422 AC: 376 AN: 890

South Asian (SAS) AF: 0.501 AC: 738 AN: 1474

European-Finnish (FIN) AF: 0.733 AC: 378 AN: 516

Middle Eastern (MID) AF: 0.318 AC: 14 AN: 44

European-Non Finnish (NFE) AF: 0.720 AC: 8574 AN: 11904

Other (OTH) AF: 0.705 AC: 713 AN: 1012

GnomAD4 genome AF: 0.704 AC: 106872 AN: 151826 Hom.: 37911 Cov.: 31 AF XY: 0.701 AC XY: 52008 AN XY: 74180

African (AFR) AF: 0.671 AC: 27763 AN: 41346

American (AMR) AF: 0.757 AC: 11558 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 2392 AN: 3464

East Asian (EAS) AF: 0.471 AC: 2420 AN: 5142

South Asian (SAS) AF: 0.535 AC: 2571 AN: 4810

European-Finnish (FIN) AF: 0.754 AC: 7926 AN: 10518

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.733 AC: 49815 AN: 67954

Other (OTH) AF: 0.676 AC: 1425 AN: 2108

Alfa AF: 0.719 Hom.: 57943

Bravo AF: 0.703

Asia WGS AF: 0.547 AC: 1903 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	0.59
DANN	Benign	0.55
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3741205; hg19: chr11-2169884;