chr11-2148913-G-A

Variant names:

• chr11-2148913-G-A
• rs1004446
• ENST00000397270.1:c.407+213C>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+213C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 594,250 control chromosomes in the GnomAD database, including 37,969 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 0.36 (10303 hom., cov: 31)
  • Exomes 𝑓: 0.35 (27666 hom.)
• Consequence: INS-IGF2 ENST00000397270.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.214
• Publications: 90 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 (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-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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.407+213C>T		intron_variant	Intron 3 of 4		NP_001035835.1
IGF2	NM_001007139.6	c.-249+213C>T		intron_variant	Intron 1 of 4		NP_001007140.2
INS-IGF2	NR_003512.4	n.466+213C>T		intron_variant	Intron 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.407+213C>T		intron_variant	Intron 3 of 4	1		ENSP00000380440.1
ENSG00000284779	ENST00000643349.2	c.254+213C>T		intron_variant	Intron 1 of 4			ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55337 AN: 151632 Hom.: 10301 Cov.: 31

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.336

GnomAD4 exome AF: 0.348 AC: 154063 AN: 442500 Hom.: 27666 Cov.: 4 AF XY: 0.343 AC XY: 79583 AN XY: 231954

African (AFR) AF: 0.408 AC: 5029 AN: 12318

American (AMR) AF: 0.275 AC: 5026 AN: 18250

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 4595 AN: 13610

East Asian (EAS) AF: 0.304 AC: 9382 AN: 30858

South Asian (SAS) AF: 0.273 AC: 12112 AN: 44306

European-Finnish (FIN) AF: 0.345 AC: 10144 AN: 29406

Middle Eastern (MID) AF: 0.262 AC: 510 AN: 1944

European-Non Finnish (NFE) AF: 0.369 AC: 98151 AN: 266054

Other (OTH) AF: 0.354 AC: 9114 AN: 25754

GnomAD4 genome AF: 0.365 AC: 55361 AN: 151750 Hom.: 10303 Cov.: 31 AF XY: 0.359 AC XY: 26611 AN XY: 74148

African (AFR) AF: 0.411 AC: 16975 AN: 41314

American (AMR) AF: 0.283 AC: 4331 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1192 AN: 3468

East Asian (EAS) AF: 0.304 AC: 1559 AN: 5128

South Asian (SAS) AF: 0.267 AC: 1284 AN: 4810

European-Finnish (FIN) AF: 0.339 AC: 3566 AN: 10508

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.372 AC: 25244 AN: 67936

Other (OTH) AF: 0.337 AC: 708 AN: 2104

Alfa AF: 0.364 Hom.: 40181

Bravo AF: 0.363

Asia WGS AF: 0.320 AC: 1113 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.8
DANN	Benign	0.24
PhyloP100		0.21
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: rs1004446; hg19: chr11-2170143;