11-2147759-G-T

Position:

• chr11-2147759-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001042376.3(INS-IGF2):​c.456C>A​(p.Ser152Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: INS-IGF2 NM_001042376.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.22

Genes affected

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]

ENSG00000284779 (HGNC:):

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0791021).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS-IGF2	NM_001042376.3	c.456C>A	p.Ser152Arg	missense_variant	4/5		NP_001035835.1
IGF2	NM_001007139.6	c.-200C>A		5_prime_UTR_variant	2/5		NP_001007140.2
INS-IGF2	NR_003512.4	n.515C>A		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1	c.456C>A	p.Ser152Arg	missense_variant	4/5	1		ENSP00000380440.1
ENSG00000284779	ENST00000643349.2	c.303C>A	p.Ser101Arg	missense_variant	2/5			ENSP00000495715.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096660 Hom.: 0 Cov.: 29 AF XY: 0.00000193 AC XY: 1 AN XY: 517914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000217

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.456C>A (p.S152R) alteration is located in exon 4 (coding exon 3) of the INS-IGF2 gene. This alteration results from a C to A substitution at nucleotide position 456, causing the serine (S) at amino acid position 152 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	1.4
DANN	Benign	0.96
DEOGEN2	Benign	0.0057	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.27	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.34	.;N
PROVEAN	Benign	-0.31	.;N
REVEL	Benign	0.19
Sift	Benign	0.39	.;T
Sift4G	Benign	0.66	.;T
Polyphen		0.0090	.;B
Vest4		0.058
MutPred		0.12		.;Loss of phosphorylation at S152 (P = 0.0312);
MVP		0.24
MPC		0.89
ClinPred		0.043	T
GERP RS		-4.9
Varity_R		0.054
gMVP		0.018

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2168989;