11-2133017-G-A

Variant names:

• chr11-2133017-G-A
• rs1858719337
• NM_000612.6:c.513C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000612.6(IGF2):​c.513C>T​(p.Ala171Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A171A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: IGF2 NM_000612.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.311
• Publications: 0 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=0.311 with no splicing effect.

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.513C>T	p.Ala171Ala	synonymous	Exon 4 of 4	NP_000603.1	P01344-1
	IGF2	NM_001127598.3		c.681C>T	p.Ala227Ala	synonymous	Exon 5 of 5	NP_001121070.1	P01344-3
	IGF2	NM_001007139.6		c.513C>T	p.Ala171Ala	synonymous	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.513C>T	p.Ala171Ala	synonymous	Exon 4 of 4	ENSP00000414497.2	P01344-1
	IGF2	ENST00000434045.6	TSL:1	c.681C>T	p.Ala227Ala	synonymous	Exon 5 of 5	ENSP00000391826.2	P01344-3
	IGF2	ENST00000381392.5	TSL:1	c.522C>T	p.Ala174Ala	synonymous	Exon 4 of 4	ENSP00000370799.1	P01344-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400106 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690632

African (AFR) AF: 0.00 AC: 0 AN: 31122

American (AMR) AF: 0.00 AC: 0 AN: 34622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23060

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37688

South Asian (SAS) AF: 0.00 AC: 0 AN: 78238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081352

Other (OTH) AF: 0.00 AC: 0 AN: 57536

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.78
PhyloP100		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs1858719337; hg19: chr11-2154247; COSMIC: COSV106096045; COSMIC: COSV106096045;