11-2148654-C-T

Variant names:

• chr11-2148654-C-T
• rs3741205
• ENST00000397270.1:c.407+472G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001042376.3(INS-IGF2):​c.407+472G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000988 in 151,876 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.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INS-IGF2 NM_001042376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.869
• Publications: 20 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042376.3. 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
	INS-IGF2	NM_001042376.3		c.407+472G>A		intron	N/A	NP_001035835.1	F8WCM5-1
	IGF2	NM_001007139.6		c.-249+472G>A		intron	N/A	NP_001007140.2	P01344-1
	IGF2-AS	NR_028043.2		n.2056C>T		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS-IGF2	ENST00000397270.1	TSL:1	c.407+472G>A		intron	N/A	ENSP00000380440.1	F8WCM5-1
	ENSG00000284779	ENST00000643349.2		c.254+472G>A		intron	N/A	ENSP00000495715.1	A0A2R8Y747
	IGF2	ENST00000481781.3	TSL:5	c.-249+472G>A		intron	N/A	ENSP00000511998.1	P01344-1

Frequencies

GnomAD3 genomes AF: 0.0000988 AC: 15 AN: 151758 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000312 AC: 6 AN: 19204 Hom.: 0 Cov.: 0 AF XY: 0.000416 AC XY: 4 AN XY: 9612

African (AFR) AF: 0.00 AC: 0 AN: 450

American (AMR) AF: 0.00163 AC: 4 AN: 2454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 384

East Asian (EAS) AF: 0.00 AC: 0 AN: 898

South Asian (SAS) AF: 0.00 AC: 0 AN: 1478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.000167 AC: 2 AN: 11958

Other (OTH) AF: 0.00 AC: 0 AN: 1012

GnomAD4 genome AF: 0.0000988 AC: 15 AN: 151876 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74204

African (AFR) AF: 0.0000484 AC: 2 AN: 41364

American (AMR) AF: 0.000523 AC: 8 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 57943

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.71
DANN	Benign	0.90
PhyloP100		-0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3741205; hg19: chr11-2169884;