rs10840452

Variant names:

• chr11-2157278-G-A
• rs10840452
• ENST00000397270.1:c.187+3507C>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.187+3507C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,206 control chromosomes in the GnomAD database, including 7,000 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 0.28 (7000 hom., cov: 33)
• Consequence: INS-IGF2 ENST00000397270.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.294
• Publications: 2 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.187+3507C>T		intron_variant	Intron 2 of 4		NP_001035835.1
INS-IGF2	NR_003512.4	n.246+3507C>T		intron_variant	Intron 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.187+3507C>T		intron_variant	Intron 2 of 4	1		ENSP00000380440.1
IGF2	ENST00000481781.3	c.-469+989C>T		intron_variant	Intron 1 of 5	5		ENSP00000511998.1
INS-IGF2	ENST00000356578.8	n.187+3507C>T		intron_variant	Intron 2 of 6	5		ENSP00000348986.4
IGF2	ENST00000476874.1	n.70+989C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42232 AN: 152088 Hom.: 6991 Cov.: 33

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.302

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

GnomAD4 genome AF: 0.278 AC: 42264 AN: 152206 Hom.: 7000 Cov.: 33 AF XY: 0.282 AC XY: 20946 AN XY: 74408

African (AFR) AF: 0.100 AC: 4161 AN: 41558

American (AMR) AF: 0.392 AC: 5998 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1093 AN: 3468

East Asian (EAS) AF: 0.122 AC: 632 AN: 5182

South Asian (SAS) AF: 0.325 AC: 1568 AN: 4824

European-Finnish (FIN) AF: 0.361 AC: 3819 AN: 10592

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23889 AN: 67982

Other (OTH) AF: 0.304 AC: 642 AN: 2114

Alfa AF: 0.304 Hom.: 1080

Bravo AF: 0.270

Asia WGS AF: 0.215 AC: 748 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.88
PhyloP100		-0.29
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: rs10840452; hg19: chr11-2178508;