ENST00000397270.1:c.188-1026A>G

Variant names:

• chr11-2150371-T-C
• rs4320932
• ENST00000397270.1:c.188-1026A>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.188-1026A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 152,120 control chromosomes in the GnomAD database, including 3,158 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 0.19 (3158 hom., cov: 32)
• Consequence: INS-IGF2 ENST00000397270.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 45 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]

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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.188-1026A>G		intron_variant	Intron 2 of 4		NP_001035835.1
INS-IGF2	NR_003512.4	n.247-1026A>G		intron_variant	Intron 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.188-1026A>G		intron_variant	Intron 2 of 4	1		ENSP00000380440.1
IGF2	ENST00000481781.3	c.-468-1026A>G		intron_variant	Intron 1 of 5	5		ENSP00000511998.1
INS-IGF2	ENST00000356578.8	n.188-1026A>G		intron_variant	Intron 2 of 6	5		ENSP00000348986.4
IGF2	ENST00000476874.1	n.71-1026A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29166 AN: 152002 Hom.: 3161 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.212

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.192 AC: 29167 AN: 152120 Hom.: 3158 Cov.: 32 AF XY: 0.197 AC XY: 14638 AN XY: 74358

African (AFR) AF: 0.130 AC: 5396 AN: 41490

American (AMR) AF: 0.166 AC: 2538 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3472

East Asian (EAS) AF: 0.526 AC: 2723 AN: 5172

South Asian (SAS) AF: 0.369 AC: 1779 AN: 4826

European-Finnish (FIN) AF: 0.191 AC: 2016 AN: 10570

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13221 AN: 67980

Other (OTH) AF: 0.212 AC: 447 AN: 2108

Alfa AF: 0.196 Hom.: 11386

Bravo AF: 0.189

Asia WGS AF: 0.407 AC: 1417 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.78
PhyloP100		0.020
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: rs4320932; hg19: chr11-2171601;