ENST00000643349.2:c.*46+1178T>C

Variant names:

• chr11-2146388-A-G
• rs1003484
• ENST00000643349.2:c.*46+1178T>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+1178T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 534,436 control chromosomes in the GnomAD database, including 129,954 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 0.68 (35297 hom., cov: 34)
  • Exomes 𝑓: 0.69 (94657 hom.)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.013).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2-AS	NR_028043.2	n.580A>G		non_coding_transcript_exon_variant	Exon 2 of 3
IGF2-AS	NR_133657.1	n.469A>G		non_coding_transcript_exon_variant	Exon 2 of 3
IGF2	NM_001007139.6	c.-7+1178T>C		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>C		intron_variant	Intron 2 of 4			ENSP00000495715.1
INS-IGF2	ENST00000397270.1	c.*404T>C		downstream_gene_variant		1		ENSP00000380440.1

Frequencies

GnomAD3 genomes AF: 0.676 AC: 102694 AN: 151982 Hom.: 35253 Cov.: 34

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.663

GnomAD2 exomes AF: 0.690 AC: 171025 AN: 247722 AF XY: 0.681

Gnomad AFR exome AF: 0.571

Gnomad AMR exome AF: 0.829

Gnomad ASJ exome AF: 0.679

Gnomad EAS exome AF: 0.453

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.731

Gnomad OTH exome AF: 0.706

GnomAD4 exome AF: 0.694 AC: 265478 AN: 382336 Hom.: 94657 Cov.: 0 AF XY: 0.680 AC XY: 148133 AN XY: 217728

African (AFR) AF: 0.558 AC: 5880 AN: 10530

American (AMR) AF: 0.828 AC: 30033 AN: 36282

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 7966 AN: 11742

East Asian (EAS) AF: 0.454 AC: 6018 AN: 13270

South Asian (SAS) AF: 0.546 AC: 36419 AN: 66740

European-Finnish (FIN) AF: 0.769 AC: 24371 AN: 31684

Middle Eastern (MID) AF: 0.614 AC: 1751 AN: 2852

European-Non Finnish (NFE) AF: 0.735 AC: 141410 AN: 192496

Other (OTH) AF: 0.695 AC: 11630 AN: 16740

GnomAD4 genome AF: 0.676 AC: 102793 AN: 152100 Hom.: 35297 Cov.: 34 AF XY: 0.674 AC XY: 50122 AN XY: 74374

African (AFR) AF: 0.573 AC: 23778 AN: 41470

American (AMR) AF: 0.742 AC: 11340 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2374 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2428 AN: 5142

South Asian (SAS) AF: 0.533 AC: 2572 AN: 4822

European-Finnish (FIN) AF: 0.757 AC: 8037 AN: 10610

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.733 AC: 49860 AN: 67982

Other (OTH) AF: 0.665 AC: 1400 AN: 2106

Alfa AF: 0.714 Hom.: 96291

Bravo AF: 0.670

Asia WGS AF: 0.544 AC: 1891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.24
DANN	Benign	0.20
PhyloP100		-2.7
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: rs1003484; hg19: chr11-2167618; COSMIC: COSV56098977; COSMIC: COSV56098977;