ENST00000434045.6:c.-4+229T>C

Variant names:

• chr11-2140628-A-G
• rs3741212
• ENST00000434045.6:c.-4+229T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000434045.6(IGF2):​c.-4+229T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 503,390 control chromosomes in the GnomAD database, including 124,797 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 0.64 (32631 hom., cov: 34)
  • Exomes 𝑓: 0.72 (92166 hom.)
• Consequence: IGF2 ENST00000434045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.305
• Publications: 24 publications found

Genes affected

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]

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]

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 (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2-AS	NR_028043.2	n.117A>G		non_coding_transcript_exon_variant	Exon 1 of 3
IGF2-AS	NR_133657.1	n.117A>G		non_coding_transcript_exon_variant	Exon 1 of 3
IGF2	NM_001127598.3	c.-4+229T>C		intron_variant	Intron 1 of 4		NP_001121070.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000284779	ENST00000643349.2	c.*47-5099T>C		intron_variant	Intron 2 of 4			ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97787 AN: 151966 Hom.: 32608 Cov.: 34

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.899

Gnomad SAS AF: 0.810

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.796

Gnomad NFE AF: 0.686

Gnomad OTH AF: 0.672

GnomAD2 exomes AF: 0.721 AC: 116531 AN: 161618 AF XY: 0.724

Gnomad AFR exome AF: 0.456

Gnomad AMR exome AF: 0.771

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.903

Gnomad FIN exome AF: 0.721

Gnomad NFE exome AF: 0.683

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.719 AC: 252600 AN: 351316 Hom.: 92166 Cov.: 0 AF XY: 0.726 AC XY: 145482 AN XY: 200446

African (AFR) AF: 0.465 AC: 3232 AN: 6954

American (AMR) AF: 0.765 AC: 21054 AN: 27528

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 8381 AN: 11860

East Asian (EAS) AF: 0.936 AC: 10674 AN: 11408

South Asian (SAS) AF: 0.801 AC: 47242 AN: 58970

European-Finnish (FIN) AF: 0.724 AC: 12709 AN: 17562

Middle Eastern (MID) AF: 0.787 AC: 1474 AN: 1872

European-Non Finnish (NFE) AF: 0.686 AC: 135966 AN: 198076

Other (OTH) AF: 0.695 AC: 11868 AN: 17086

GnomAD4 genome AF: 0.643 AC: 97849 AN: 152074 Hom.: 32631 Cov.: 34 AF XY: 0.654 AC XY: 48624 AN XY: 74358

African (AFR) AF: 0.462 AC: 19149 AN: 41480

American (AMR) AF: 0.733 AC: 11210 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 2485 AN: 3466

East Asian (EAS) AF: 0.899 AC: 4627 AN: 5144

South Asian (SAS) AF: 0.810 AC: 3910 AN: 4826

European-Finnish (FIN) AF: 0.727 AC: 7689 AN: 10582

Middle Eastern (MID) AF: 0.801 AC: 234 AN: 292

European-Non Finnish (NFE) AF: 0.686 AC: 46627 AN: 67956

Other (OTH) AF: 0.673 AC: 1424 AN: 2116

Alfa AF: 0.679 Hom.: 52064

Bravo AF: 0.634

Asia WGS AF: 0.801 AC: 2778 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.7
DANN	Benign	0.57
PhyloP100		-0.30
PromoterAI		-0.0075	Neutral
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: rs3741212; hg19: chr11-2161858;