11-2152217-T-G

Variant names:

• chr11-2152217-T-G
• rs7924316
• ENST00000397270.1:c.188-2872A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000397270.1(INS-IGF2):​c.188-2872A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 152,060 control chromosomes in the GnomAD database, including 19,445 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 0.50 (19445 hom., cov: 33)
• Consequence: INS-IGF2 ENST00000397270.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.458
• Publications: 37 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.188-2872A>C		intron_variant	Intron 2 of 4		NP_001035835.1
INS-IGF2	NR_003512.4	n.247-2872A>C		intron_variant	Intron 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.188-2872A>C		intron_variant	Intron 2 of 4	1		ENSP00000380440.1
IGF2	ENST00000481781.3	c.-468-2872A>C		intron_variant	Intron 1 of 5	5		ENSP00000511998.1
INS-IGF2	ENST00000356578.8	n.188-2872A>C		intron_variant	Intron 2 of 6	5		ENSP00000348986.4
IGF2	ENST00000476874.1	n.71-2872A>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75535 AN: 151944 Hom.: 19413 Cov.: 33

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.510

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

GnomAD4 genome AF: 0.497 AC: 75611 AN: 152060 Hom.: 19445 Cov.: 33 AF XY: 0.500 AC XY: 37191 AN XY: 74330

African (AFR) AF: 0.369 AC: 15316 AN: 41462

American (AMR) AF: 0.599 AC: 9160 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3472

East Asian (EAS) AF: 0.418 AC: 2157 AN: 5166

South Asian (SAS) AF: 0.481 AC: 2320 AN: 4820

European-Finnish (FIN) AF: 0.588 AC: 6216 AN: 10574

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37123 AN: 67974

Other (OTH) AF: 0.514 AC: 1083 AN: 2108

Alfa AF: 0.530 Hom.: 36129

Bravo AF: 0.491

Asia WGS AF: 0.453 AC: 1576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.45
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7924316; hg19: chr11-2173447;