11-2147784-A-G

Position:

• chr11-2147784-A-G

Variant summary

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

The NM_001007139.6(IGF2):​c.-225T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,247,656 control chromosomes in the GnomAD database, including 137,657 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 0.40 (14052 hom., cov: 31)
  • Exomes 𝑓: 0.47 (123605 hom.)
• Consequence: IGF2 NM_001007139.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.489

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 (MetaRNN=2.988811E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2	NM_001007139.6	c.-225T>C		5_prime_UTR_premature_start_codon_gain_variant	2/5		NP_001007140.2
INS-IGF2	NM_001042376.3	c.431T>C	p.Leu144Pro	missense_variant	4/5		NP_001035835.1
IGF2	NM_001007139.6	c.-225T>C		5_prime_UTR_variant	2/5		NP_001007140.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.431T>C	p.Leu144Pro	missense_variant	4/5	1		ENSP00000380440.1
ENSG00000284779	ENST00000643349.2	c.278T>C	p.Leu93Pro	missense_variant	2/5			ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61133 AN: 151726 Hom.: 14036 Cov.: 31

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.417

GnomAD3 exomes AF: 0.491 AC: 11376 AN: 23166 Hom.: 2964 AF XY: 0.503 AC XY: 5182 AN XY: 10296

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.400

Gnomad SAS exome AF: 0.307

Gnomad FIN exome AF: 0.583

Gnomad NFE exome AF: 0.474

Gnomad OTH exome AF: 0.460

GnomAD4 exome AF: 0.471 AC: 515905 AN: 1095808 Hom.: 123605 Cov.: 37 AF XY: 0.470 AC XY: 243404 AN XY: 517460

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.574

Gnomad4 ASJ exome AF: 0.452

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.353

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.478

Gnomad4 OTH exome AF: 0.436

GnomAD4 genome AF: 0.403 AC: 61163 AN: 151848 Hom.: 14052 Cov.: 31 AF XY: 0.409 AC XY: 30329 AN XY: 74218

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.539

Gnomad4 ASJ AF: 0.462

Gnomad4 EAS AF: 0.376

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.485

Gnomad4 OTH AF: 0.417

Alfa AF: 0.463 Hom.: 26845

Bravo AF: 0.392

TwinsUK AF: 0.482 AC: 1787

ALSPAC AF: 0.475 AC: 1831

ESP6500AA AF: 0.167 AC: 560

ESP6500EA AF: 0.430 AC: 3133

ExAC AF: 0.276 AC: 10533

Asia WGS AF: 0.359 AC: 1247 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.000030	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;N
PROVEAN	Benign	-0.65	.;N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.36	.;B
Vest4		0.16
MPC		1.2
ClinPred		0.045	T
GERP RS		1.1
Varity_R		0.25
gMVP		0.47

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: rs10770125; hg19: chr11-2169014; COSMIC: COSV56098292; COSMIC: COSV56098292;