chr11-2146388-A-T

Variant names:

• chr11-2146388-A-T
• rs1003484
• ENST00000643349.2:c.*46+1178T>A

Variant summary

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

The ENST00000643349.2(ENSG00000284779):​c.*46+1178T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000284779 ENST00000643349.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.75
• Publications: 18 publications found

Genes affected

ENSG00000284779 (HGNC:):

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]

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]

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 (REVEL=0.041).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2-AS	NR_028043.2	n.580A>T		non_coding_transcript_exon_variant	Exon 2 of 3
IGF2-AS	NR_133657.1	n.469A>T		non_coding_transcript_exon_variant	Exon 2 of 3
IGF2	NM_001007139.6	c.-7+1178T>A		intron_variant	Intron 2 of 4		NP_001007140.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000284779	ENST00000643349.2	c.*46+1178T>A		intron_variant	Intron 2 of 4			ENSP00000495715.1
INS-IGF2	ENST00000397270.1	c.*404T>A		downstream_gene_variant		1		ENSP00000380440.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000261 AC: 1 AN: 382476 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 217796

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10532

American (AMR) AF: 0.00 AC: 0 AN: 36294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11742

East Asian (EAS) AF: 0.00 AC: 0 AN: 13274

South Asian (SAS) AF: 0.00 AC: 0 AN: 66754

European-Finnish (FIN) AF: 0.0000315 AC: 1 AN: 31732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2858

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 192540

Other (OTH) AF: 0.00 AC: 0 AN: 16750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 96291

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.23
DANN	Benign	0.35
PhyloP100		-2.7

Splicing

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

Other links and lift over

dbSNP: rs1003484; hg19: chr11-2167618;