chr11-2147784-A-G

Variant names:

• chr11-2147784-A-G
• rs10770125
• ENST00000397270.1:c.431T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 44 publications found

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]

IGF2-AS (HGNC:14062): (IGF2 antisense RNA) This gene is expressed in antisense to the insulin-like growth factor 2 (IGF2) gene and is imprinted and paternally expressed. It is thought to be non-coding because the putative protein is not conserved and translation is predicted to trigger nonsense mediated decay (NMD). Transcripts from this gene are produced in tumors and may function to suppress cell growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007139.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2	NM_001007139.6		c.-225T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001007140.2
	INS-IGF2	NM_001042376.3		c.431T>C	p.Leu144Pro	missense	Exon 4 of 5	NP_001035835.1
	IGF2	NM_001007139.6		c.-225T>C		5_prime_UTR	Exon 2 of 5	NP_001007140.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS-IGF2	ENST00000397270.1	TSL:1	c.431T>C	p.Leu144Pro	missense	Exon 4 of 5	ENSP00000380440.1
	ENSG00000284779	ENST00000643349.2		c.278T>C	p.Leu93Pro	missense	Exon 2 of 5	ENSP00000495715.1
	IGF2	ENST00000481781.3	TSL:5	c.-225T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	ENSP00000511998.1

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

GnomAD2 exomes AF: 0.491 AC: 11376 AN: 23166 AF XY: 0.503

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 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

African (AFR) AF: 0.161 AC: 3710 AN: 23042

American (AMR) AF: 0.574 AC: 4838 AN: 8434

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 6500 AN: 14392

East Asian (EAS) AF: 0.467 AC: 12389 AN: 26542

South Asian (SAS) AF: 0.353 AC: 6931 AN: 19654

European-Finnish (FIN) AF: 0.574 AC: 20240 AN: 35272

Middle Eastern (MID) AF: 0.446 AC: 1953 AN: 4380

European-Non Finnish (NFE) AF: 0.478 AC: 440184 AN: 920162

Other (OTH) AF: 0.436 AC: 19160 AN: 43930

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

African (AFR) AF: 0.177 AC: 7331 AN: 41430

American (AMR) AF: 0.539 AC: 8230 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1603 AN: 3468

East Asian (EAS) AF: 0.376 AC: 1921 AN: 5110

South Asian (SAS) AF: 0.348 AC: 1676 AN: 4816

European-Finnish (FIN) AF: 0.563 AC: 5942 AN: 10554

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.485 AC: 32901 AN: 67884

Other (OTH) AF: 0.417 AC: 879 AN: 2108

Alfa AF: 0.458 Hom.: 62789

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 v4.9

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
MetaRNN	Benign	0.000030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.49
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
Mutation Taster		=97/3	polymorphism (auto)

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