11-2140628-A-G

Position:

• chr11-2140628-A-G

Variant summary

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

The NM_001127598.3(IGF2):​c.-4+229T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 503,390 control chromosomes in the GnomAD database, including 124,797 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 0.64 (32631 hom., cov: 34)
  • Exomes 𝑓: 0.72 (92166 hom.)
• Consequence: IGF2 NM_001127598.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.305

Genes affected

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]

ENSG00000284779 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2	NM_001127598.3	c.-4+229T>C		intron_variant			NP_001121070.1
IGF2	NM_001007139.6	c.-6-5099T>C		intron_variant			NP_001007140.2
IGF2	NM_001291862.3	c.-7+229T>C		intron_variant			NP_001278791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000284779	ENST00000643349.2	c.*47-5099T>C		intron_variant				ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97787 AN: 151966 Hom.: 32608 Cov.: 34

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.899

Gnomad SAS AF: 0.810

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.796

Gnomad NFE AF: 0.686

Gnomad OTH AF: 0.672

GnomAD3 exomes AF: 0.721 AC: 116531 AN: 161618 Hom.: 42709 AF XY: 0.724 AC XY: 66590 AN XY: 92028

Gnomad AFR exome AF: 0.456

Gnomad AMR exome AF: 0.771

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.903

Gnomad SAS exome AF: 0.810

Gnomad FIN exome AF: 0.721

Gnomad NFE exome AF: 0.683

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.719 AC: 252600 AN: 351316 Hom.: 92166 Cov.: 0 AF XY: 0.726 AC XY: 145482 AN XY: 200446

Gnomad4 AFR exome AF: 0.465

Gnomad4 AMR exome AF: 0.765

Gnomad4 ASJ exome AF: 0.707

Gnomad4 EAS exome AF: 0.936

Gnomad4 SAS exome AF: 0.801

Gnomad4 FIN exome AF: 0.724

Gnomad4 NFE exome AF: 0.686

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.643 AC: 97849 AN: 152074 Hom.: 32631 Cov.: 34 AF XY: 0.654 AC XY: 48624 AN XY: 74358

Gnomad4 AFR AF: 0.462

Gnomad4 AMR AF: 0.733

Gnomad4 ASJ AF: 0.717

Gnomad4 EAS AF: 0.899

Gnomad4 SAS AF: 0.810

Gnomad4 FIN AF: 0.727

Gnomad4 NFE AF: 0.686

Gnomad4 OTH AF: 0.673

Alfa AF: 0.684 Hom.: 36107

Bravo AF: 0.634

Asia WGS AF: 0.801 AC: 2778 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.7
DANN	Benign	0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3741212; hg19: chr11-2161858;