Genetic Variant ENST00000643349.2:c.*46+1178T>A (chr11-2146388-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.75

Publications

18 publications found

Variant links:

Genes affected

ENSG00000284779 (HGNC:):

ENSG00000284779 links:

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-AS links:

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]

IGF2 links:

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]

INS-IGF2 links:

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ACMG classification

Classification was made for transcript

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	Effect	Exon rank	Protein	UniProt
IGF2-AS	NR_028043.2 link	n.580A>T	non_coding_transcript_exon_variant	Exon 2 of 3
IGF2-AS	NR_133657.1 link	n.469A>T	non_coding_transcript_exon_variant	Exon 2 of 3
IGF2	NM_001007139.6 link	c.-7+1178T>A	intron_variant	Intron 2 of 4	NP_001007140.2	P01344-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000284779	ENST00000643349.2 link	c.*46+1178T>A		intron_variant	Intron 2 of 4			ENSP00000495715.1		A0A2R8Y747
INS-IGF2	ENST00000397270.1 link	c.*404T>A		downstream_gene_variant		1		ENSP00000380440.1		F8WCM5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000261

AC:

AN:

382476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

217796

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

10532

American (AMR)

AF:

0.00

AC:

AN:

36294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11742

East Asian (EAS)

AF:

0.00

AC:

AN:

13274

South Asian (SAS)

AF:

0.00

AC:

AN:

66754

European-Finnish (FIN)

AF:

0.0000315

AC:

AN:

31732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2858

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

192540

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

(source)

DANN

Benign

0.35

PhyloP100

-2.7

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over