rs1003484

Positions:

• chr11-2146388-A-G
• chr11-2146388-A-T

Variant summary

Our verdict is Benign. Variant got -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: ENST00000643349.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.75

Genes affected

(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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• 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/exons	MANE	UniProt
IGF2-AS	NR_028043.2	n.580A>G		non_coding_transcript_exon_variant	2/3
INS-IGF2	NR_003512.4	n.708+1178T>C		intron_variant, non_coding_transcript_variant
IGF2	NM_001007139.6	c.-7+1178T>C		intron_variant
IGF2-AS	NR_133657.1	n.469A>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000643349.2	c.*46+1178T>C		intron_variant				P1
IGF2-AS	ENST00000381361.4	n.575A>G		non_coding_transcript_exon_variant	2/3	2

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

GnomAD3 exomes AF: 0.690 AC: 171025 AN: 247722 Hom.: 60824 AF XY: 0.681 AC XY: 91727 AN XY: 134656

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 SAS exome AF: 0.532

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

Gnomad4 AFR exome AF: 0.558

Gnomad4 AMR exome AF: 0.828

Gnomad4 ASJ exome AF: 0.678

Gnomad4 EAS exome AF: 0.454

Gnomad4 SAS exome AF: 0.546

Gnomad4 FIN exome AF: 0.769

Gnomad4 NFE exome AF: 0.735

Gnomad4 OTH exome AF: 0.695

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

Gnomad4 AFR AF: 0.573

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.684

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.533

Gnomad4 FIN AF: 0.757

Gnomad4 NFE AF: 0.733

Gnomad4 OTH AF: 0.665

Alfa AF: 0.712 Hom.: 65359

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1003484; hg19: chr11-2167618; COSMIC: COSV56098977; COSMIC: COSV56098977;