rs3741211

Positions:

• chr11-2147880-A-G
• chr11-2147880-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001042376.3(INS-IGF2):​c.408-73T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,112,480 control chromosomes in the GnomAD database, including 79,314 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 (9993 hom., cov: 30)
  • Exomes 𝑓: 0.38 (69321 hom.)
• Consequence: INS-IGF2 NM_001042376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.408-73T>C		intron_variant			NP_001035835.1
IGF2	NM_001007139.6	c.-248-73T>C		intron_variant			NP_001007140.2
IGF2-AS	NR_028043.2	n.1282A>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.408-73T>C		intron_variant		1		ENSP00000380440.1
ENSG00000284779	ENST00000643349.2	c.255-73T>C		intron_variant				ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54492 AN: 151512 Hom.: 9989 Cov.: 30

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.378 AC: 363219 AN: 960846 Hom.: 69321 Cov.: 14 AF XY: 0.377 AC XY: 172250 AN XY: 456882

Gnomad4 AFR exome AF: 0.394

Gnomad4 AMR exome AF: 0.278

Gnomad4 ASJ exome AF: 0.325

Gnomad4 EAS exome AF: 0.294

Gnomad4 SAS exome AF: 0.268

Gnomad4 FIN exome AF: 0.346

Gnomad4 NFE exome AF: 0.387

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.360 AC: 54521 AN: 151634 Hom.: 9993 Cov.: 30 AF XY: 0.354 AC XY: 26221 AN XY: 74128

Gnomad4 AFR AF: 0.395

Gnomad4 AMR AF: 0.282

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.282

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.340

Gnomad4 NFE AF: 0.372

Gnomad4 OTH AF: 0.332

Alfa AF: 0.364 Hom.: 9787

Bravo AF: 0.356

Asia WGS AF: 0.313 AC: 1091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.7
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs3741211; hg19: chr11-2169110;