rs10840442

Variant names:

• chr11-2150692-T-C
• rs10840442
• ENST00000397270.1:c.188-1347A>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.188-1347A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,096 control chromosomes in the GnomAD database, including 2,524 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 0.17 (2524 hom., cov: 32)
• Consequence: INS-IGF2 ENST00000397270.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.280
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.188-1347A>G		intron_variant	Intron 2 of 4		NP_001035835.1
INS-IGF2	NR_003512.4	n.247-1347A>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.188-1347A>G		intron_variant	Intron 2 of 4	1		ENSP00000380440.1
IGF2	ENST00000481781.3	c.-468-1347A>G		intron_variant	Intron 1 of 5	5		ENSP00000511998.1
INS-IGF2	ENST00000356578.8	n.188-1347A>G		intron_variant	Intron 2 of 6	5		ENSP00000348986.4
IGF2	ENST00000476874.1	n.71-1347A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26387 AN: 151978 Hom.: 2519 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.155

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

GnomAD4 genome AF: 0.174 AC: 26428 AN: 152096 Hom.: 2524 Cov.: 32 AF XY: 0.173 AC XY: 12843 AN XY: 74352

African (AFR) AF: 0.171 AC: 7114 AN: 41490

American (AMR) AF: 0.117 AC: 1784 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 434 AN: 3468

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5182

South Asian (SAS) AF: 0.138 AC: 665 AN: 4818

European-Finnish (FIN) AF: 0.229 AC: 2423 AN: 10564

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13431 AN: 67978

Other (OTH) AF: 0.158 AC: 333 AN: 2110

Alfa AF: 0.179 Hom.: 5454

Bravo AF: 0.164

Asia WGS AF: 0.0890 AC: 312 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	0.60
DANN	Benign	0.80
PhyloP100		-0.28
Mutation Taster		=100/0	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: rs10840442; hg19: chr11-2171922;