ENST00000643349.2:c.*46+5686A>C

Variant names:

• chr11-2141880-T-G
• rs4244808
• ENST00000643349.2:c.*46+5686A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000643349.2(ENSG00000284779):​c.*46+5686A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 152,128 control chromosomes in the GnomAD database, including 13,899 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 0.41 (13899 hom., cov: 33)
• Consequence: ENSG00000284779 ENST00000643349.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.333
• Publications: 20 publications found

Genes affected

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]

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]

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 (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000643349.2. 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.-7+5686A>C		intron	N/A	NP_001007140.2
	INS-IGF2	NR_003512.4		n.708+5686A>C		intron	N/A
	IGF2-AS	NR_028043.2		n.436+933T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000284779	ENST00000643349.2		c.*46+5686A>C		intron	N/A	ENSP00000495715.1
	IGF2	ENST00000481781.3	TSL:5	c.-7+5686A>C		intron	N/A	ENSP00000511998.1
	IGF2	ENST00000695541.1		c.-7+5686A>C		intron	N/A	ENSP00000511997.1

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62426 AN: 152010 Hom.: 13874 Cov.: 33

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.417

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.411 AC: 62481 AN: 152128 Hom.: 13899 Cov.: 33 AF XY: 0.417 AC XY: 31004 AN XY: 74372

African (AFR) AF: 0.243 AC: 10073 AN: 41506

American (AMR) AF: 0.535 AC: 8185 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1621 AN: 3472

East Asian (EAS) AF: 0.364 AC: 1889 AN: 5190

South Asian (SAS) AF: 0.340 AC: 1640 AN: 4822

European-Finnish (FIN) AF: 0.542 AC: 5723 AN: 10556

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31923 AN: 67984

Other (OTH) AF: 0.417 AC: 880 AN: 2110

Alfa AF: 0.464 Hom.: 16826

Bravo AF: 0.403

Asia WGS AF: 0.353 AC: 1228 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.62
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4244808; hg19: chr11-2163110;