ENST00000643349.2:c.*46+1253A>C

Variant names:

• chr11-2146313-T-G
• rs1003483
• ENST00000643349.2:c.*46+1253A>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+1253A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 535,818 control chromosomes in the GnomAD database, including 58,442 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 0.40 (13961 hom., cov: 34)
  • Exomes 𝑓: 0.47 (44481 hom.)
• Consequence: ENSG00000284779 ENST00000643349.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 34 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=0.014).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2-AS	NR_028043.2	n.505T>G		non_coding_transcript_exon_variant	Exon 2 of 3
IGF2	NM_001007139.6	c.-7+1253A>C		intron_variant	Intron 2 of 4		NP_001007140.2
INS-IGF2	NR_003512.4	n.708+1253A>C		intron_variant	Intron 4 of 6
IGF2-AS	NR_133657.1	n.437-43T>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000284779	ENST00000643349.2	c.*46+1253A>C		intron_variant	Intron 2 of 4			ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60682 AN: 152048 Hom.: 13946 Cov.: 34

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.415

GnomAD2 exomes AF: 0.465 AC: 115517 AN: 248336 AF XY: 0.459

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.637

Gnomad ASJ exome AF: 0.448

Gnomad EAS exome AF: 0.356

Gnomad FIN exome AF: 0.577

Gnomad NFE exome AF: 0.483

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.469 AC: 180029 AN: 383652 Hom.: 44481 Cov.: 0 AF XY: 0.459 AC XY: 100368 AN XY: 218456

African (AFR) AF: 0.162 AC: 1716 AN: 10576

American (AMR) AF: 0.634 AC: 23037 AN: 36316

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 5264 AN: 11774

East Asian (EAS) AF: 0.368 AC: 4949 AN: 13436

South Asian (SAS) AF: 0.361 AC: 24110 AN: 66740

European-Finnish (FIN) AF: 0.577 AC: 18289 AN: 31714

Middle Eastern (MID) AF: 0.431 AC: 1234 AN: 2860

European-Non Finnish (NFE) AF: 0.485 AC: 93877 AN: 193404

Other (OTH) AF: 0.449 AC: 7553 AN: 16832

GnomAD4 genome AF: 0.399 AC: 60714 AN: 152166 Hom.: 13961 Cov.: 34 AF XY: 0.405 AC XY: 30143 AN XY: 74392

African (AFR) AF: 0.166 AC: 6897 AN: 41524

American (AMR) AF: 0.534 AC: 8164 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1600 AN: 3470

East Asian (EAS) AF: 0.375 AC: 1930 AN: 5152

South Asian (SAS) AF: 0.348 AC: 1680 AN: 4822

European-Finnish (FIN) AF: 0.564 AC: 5976 AN: 10598

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32916 AN: 67990

Other (OTH) AF: 0.414 AC: 877 AN: 2116

Alfa AF: 0.462 Hom.: 22408

Bravo AF: 0.387

Asia WGS AF: 0.360 AC: 1249 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.0
DANN	Benign	0.89
PhyloP100		-1.0
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: rs1003483; hg19: chr11-2167543; COSMIC: COSV56097715; COSMIC: COSV56097715;