chr11-2133012-G-A

Variant names:

• chr11-2133012-G-A
• rs1050342
• NM_000612.6:c.518C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000612.6(IGF2):​c.518C>T​(p.Pro173Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000388 in 1,545,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P173Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: IGF2 NM_000612.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19328806).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000612.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2	NM_000612.6	MANE Select	c.518C>T	p.Pro173Leu	missense	Exon 4 of 4	NP_000603.1	P01344-1
	IGF2	NM_001127598.3		c.686C>T	p.Pro229Leu	missense	Exon 5 of 5	NP_001121070.1	P01344-3
	IGF2	NM_001007139.6		c.518C>T	p.Pro173Leu	missense	Exon 5 of 5	NP_001007140.2	P01344-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2	ENST00000416167.7	TSL:1 MANE Select	c.518C>T	p.Pro173Leu	missense	Exon 4 of 4	ENSP00000414497.2	P01344-1
	IGF2	ENST00000434045.6	TSL:1	c.686C>T	p.Pro229Leu	missense	Exon 5 of 5	ENSP00000391826.2	P01344-3
	IGF2	ENST00000381392.5	TSL:1	c.527C>T	p.Pro176Leu	missense	Exon 4 of 4	ENSP00000370799.1	P01344-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152046 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1393674 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 686838

African (AFR) AF: 0.0000324 AC: 1 AN: 30908

American (AMR) AF: 0.00 AC: 0 AN: 34078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22728

East Asian (EAS) AF: 0.00 AC: 0 AN: 37444

South Asian (SAS) AF: 0.00 AC: 0 AN: 77214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077804

Other (OTH) AF: 0.00 AC: 0 AN: 57244

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74256

African (AFR) AF: 0.0000483 AC: 2 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000268 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.22
Sift	Benign	0.16	T
Sift4G	Benign	0.23	T
Polyphen		0.10	B
Vest4		0.050
MVP		0.92
MPC		0.70
ClinPred		0.13	T
GERP RS		0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.046
gMVP		0.17
Mutation Taster		=88/12	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: rs1050342; hg19: chr11-2154242;