11-2148634-T-C

Position:

• chr11-2148634-T-C

Variant summary

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

The NM_001042376.3(INS-IGF2):​c.407+492A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 162,972 control chromosomes in the GnomAD database, including 10,480 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 0.35 (9595 hom., cov: 32)
  • Exomes 𝑓: 0.37 (885 hom.)
• Consequence: INS-IGF2 NM_001042376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.407+492A>G		intron_variant			NP_001035835.1
IGF2	NM_001007139.6	c.-249+492A>G		intron_variant			NP_001007140.2
IGF2-AS	NR_028043.2	n.2036T>C		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.407+492A>G		intron_variant		1		ENSP00000380440.1
ENSG00000284779	ENST00000643349.2	c.254+492A>G		intron_variant				ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52884 AN: 151836 Hom.: 9563 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.349

GnomAD4 exome AF: 0.372 AC: 4098 AN: 11016 Hom.: 885 Cov.: 0 AF XY: 0.361 AC XY: 2009 AN XY: 5562

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.476

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.450

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.349 AC: 52967 AN: 151956 Hom.: 9595 Cov.: 32 AF XY: 0.351 AC XY: 26074 AN XY: 74244

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.476

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.413

Gnomad4 NFE AF: 0.359

Gnomad4 OTH AF: 0.349

Alfa AF: 0.355 Hom.: 6651

Bravo AF: 0.352

Asia WGS AF: 0.237 AC: 822 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	5.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3741206; hg19: chr11-2169864;