11-2143569-G-C

Variant names:

• chr11-2143569-G-C
• rs4366464
• ENST00000643349.2:c.*46+3997C>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001007139.6(IGF2):​c.-7+3997C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.888 in 151,972 control chromosomes in the GnomAD database, including 60,364 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 0.89 (60364 hom., cov: 29)
• Consequence: IGF2 NM_001007139.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2	NM_001007139.6	c.-7+3997C>G		intron_variant	Intron 2 of 4		NP_001007140.2
INS-IGF2	NR_003512.4	n.708+3997C>G		intron_variant	Intron 4 of 6
IGF2-AS	NR_028043.2	n.436+2622G>C		intron_variant	Intron 1 of 2
IGF2-AS	NR_133657.1	n.436+2622G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000284779	ENST00000643349.2	c.*46+3997C>G		intron_variant	Intron 2 of 4			ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.888 AC: 134802 AN: 151860 Hom.: 60320 Cov.: 29

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.930

Gnomad ASJ AF: 0.930

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.940

Gnomad MID AF: 0.914

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.879

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

GnomAD4 genome AF: 0.888 AC: 134903 AN: 151972 Hom.: 60364 Cov.: 29 AF XY: 0.891 AC XY: 66179 AN XY: 74272

Gnomad4 AFR AF: 0.765

Gnomad4 AMR AF: 0.930

Gnomad4 ASJ AF: 0.930

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.957

Gnomad4 FIN AF: 0.940

Gnomad4 NFE AF: 0.928

Gnomad4 OTH AF: 0.881

Alfa AF: 0.908 Hom.: 3090

Bravo AF: 0.879

Asia WGS AF: 0.973 AC: 3383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.41
DANN	Benign	0.31

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4366464; hg19: chr11-2164799;