NM_000612.6:c.535C>G

Variant names:

• chr11-2132995-G-C
• rs1014211286
• NM_000612.6:c.535C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000612.6(IGF2):​c.535C>G​(p.Arg179Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,375,660 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: IGF2 NM_000612.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.180
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08161712).

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.535C>G	p.Arg179Gly	missense	Exon 4 of 4	NP_000603.1	P01344-1
	IGF2	NM_001127598.3		c.703C>G	p.Arg235Gly	missense	Exon 5 of 5	NP_001121070.1	P01344-3
	IGF2	NM_001007139.6		c.535C>G	p.Arg179Gly	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.535C>G	p.Arg179Gly	missense	Exon 4 of 4	ENSP00000414497.2	P01344-1
	IGF2	ENST00000434045.6	TSL:1	c.703C>G	p.Arg235Gly	missense	Exon 5 of 5	ENSP00000391826.2	P01344-3
	IGF2	ENST00000381392.5	TSL:1	c.544C>G	p.Arg182Gly	missense	Exon 4 of 4	ENSP00000370799.1	P01344-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1375660 Hom.: 0 Cov.: 30 AF XY: 0.00000296 AC XY: 2 AN XY: 676038

African (AFR) AF: 0.00 AC: 0 AN: 30310

American (AMR) AF: 0.00 AC: 0 AN: 31622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21522

East Asian (EAS) AF: 0.00 AC: 0 AN: 37018

South Asian (SAS) AF: 0.0000135 AC: 1 AN: 74128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5362

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069212

Other (OTH) AF: 0.00 AC: 0 AN: 56532

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.7
DANN	Benign	0.81
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.31	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.18
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		0.011	B
Vest4		0.089
MutPred		0.15		Loss of stability (P = 0.0111)
MVP		0.74
MPC		0.92
ClinPred		0.086	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.18
Mutation Taster		=95/5	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: rs1014211286; hg19: chr11-2154225; COSMIC: COSV56101424; COSMIC: COSV56101424;