11-2146751-G-A

Position:

• chr11-2146751-G-A

Variant summary

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

The NM_001042376.3(INS-IGF2):​c.*47-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 254,874 control chromosomes in the GnomAD database, including 12,393 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (5368 hom., cov: 33)
  • Exomes 𝑓: 0.35 (7025 hom.)
• Consequence: INS-IGF2 NM_001042376.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.745

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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.*47-6C>T		splice_region_variant, intron_variant			NP_001035835.1
IGF2	NM_001007139.6	c.-7+815C>T		intron_variant			NP_001007140.2
INS-IGF2	NR_003512.4	n.708+815C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.*47-6C>T		splice_region_variant, intron_variant		1		ENSP00000380440.1
ENSG00000284779	ENST00000643349.2	c.*46+815C>T		intron_variant				ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39157 AN: 152004 Hom.: 5370 Cov.: 33

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.292

GnomAD4 exome AF: 0.348 AC: 35739 AN: 102752 Hom.: 7025 Cov.: 0 AF XY: 0.367 AC XY: 20413 AN XY: 55552

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.339

Gnomad4 EAS exome AF: 0.632

Gnomad4 SAS exome AF: 0.506

Gnomad4 FIN exome AF: 0.280

Gnomad4 NFE exome AF: 0.298

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.257 AC: 39149 AN: 152122 Hom.: 5368 Cov.: 33 AF XY: 0.262 AC XY: 19496 AN XY: 74362

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.530

Gnomad4 SAS AF: 0.463

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.290

Alfa AF: 0.272 Hom.: 6211

Bravo AF: 0.253

Asia WGS AF: 0.442 AC: 1536 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.27
DANN	Benign	0.67

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: rs2239681; hg19: chr11-2167981;