11-2131409-C-T

Variant names:

• chr11-2131409-C-T
• rs1065687
• NM_000612.6:c.*1578G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000612.6(IGF2):​c.*1578G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0374 in 233,074 control chromosomes in the GnomAD database, including 249 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 0.037 (156 hom., cov: 34)
  • Exomes 𝑓: 0.038 (93 hom.)
• Consequence: IGF2 NM_000612.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.452
• Publications: 2 publications found

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2	NM_000612.6	c.*1578G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000416167.7	NP_000603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2	ENST00000416167.7	c.*1578G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_000612.6	ENSP00000414497.2
IGF2	ENST00000381406.8	c.*1578G>A		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000370813.4
ENSG00000284779	ENST00000643349.2	c.*2173G>A		3_prime_UTR_variant	Exon 5 of 5			ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5612 AN: 151924 Hom.: 158 Cov.: 34

Gnomad AFR AF: 0.00975

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0297

GnomAD4 exome AF: 0.0384 AC: 3113 AN: 81030 Hom.: 93 Cov.: 0 AF XY: 0.0383 AC XY: 1427 AN XY: 37254

African (AFR) AF: 0.00847 AC: 33 AN: 3896

American (AMR) AF: 0.0160 AC: 40 AN: 2500

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 117 AN: 5124

East Asian (EAS) AF: 0.00 AC: 0 AN: 11412

South Asian (SAS) AF: 0.0225 AC: 16 AN: 710

European-Finnish (FIN) AF: 0.118 AC: 8 AN: 68

Middle Eastern (MID) AF: 0.00405 AC: 2 AN: 494

European-Non Finnish (NFE) AF: 0.0527 AC: 2636 AN: 50052

Other (OTH) AF: 0.0385 AC: 261 AN: 6774

GnomAD4 genome AF: 0.0369 AC: 5611 AN: 152044 Hom.: 156 Cov.: 34 AF XY: 0.0373 AC XY: 2776 AN XY: 74360

African (AFR) AF: 0.00972 AC: 402 AN: 41342

American (AMR) AF: 0.0175 AC: 268 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00974 AC: 47 AN: 4824

European-Finnish (FIN) AF: 0.0725 AC: 769 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0578 AC: 3929 AN: 68012

Other (OTH) AF: 0.0294 AC: 62 AN: 2110

Alfa AF: 0.0489 Hom.: 195

Bravo AF: 0.0325

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.78
PhyloP100		-0.45
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism

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: rs1065687; hg19: chr11-2152639;