Genetic Variant NM_000612.6:c.517C>A (chr11-2133013-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000612.6(IGF2):c.517C>A(p.Pro173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P173Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

IGF2
NM_000612.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0760

Variant links:

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]

IGF2 links:

ENSG00000284779 (HGNC:):

ENSG00000284779 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 made for transcript

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=0.08545312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2	NM_000612.6 link	c.517C>A	p.Pro173Thr	missense_variant	Exon 4 of 4	ENST00000416167.7	NP_000603.1	P01344-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGF2	ENST00000416167.7 link	c.517C>A	p.Pro173Thr	missense_variant	Exon 4 of 4	1	NM_000612.6	ENSP00000414497.2	P01344-1
IGF2	ENST00000381392.5 link	c.526C>A	p.Pro176Thr	missense_variant	Exon 4 of 4	1		ENSP00000370799.1	P01344-2
IGF2	ENST00000381406.8 link	c.526C>A	p.Pro176Thr	missense_variant	Exon 4 of 4	2		ENSP00000370813.4	P01344-2
ENSG00000284779	ENST00000643349 link	c.*524C>A		3_prime_UTR_variant	Exon 5 of 5			ENSP00000495715.1	A0A2R8Y747

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398522

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689512

show subpopulations

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:

9.26e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.4

DANN

Benign

0.73

DEOGEN2

Benign

0.25

T;.;T;T;.;.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.76

.;.;.;.;T;T;.;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.085

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.8

L;.;L;L;.;.;L;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.67

N;N;N;.;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.37

T;D;T;.;D;D;T;T

Sift4G

Benign

0.53

T;T;T;.;T;T;T;T

Polyphen

0.22

B;.;B;B;.;.;B;B

Vest4

0.052

MutPred

0.12

Loss of catalytic residue at P172 (P = 0.0131);.;Loss of catalytic residue at P172 (P = 0.0131);Loss of catalytic residue at P172 (P = 0.0131);.;.;Loss of catalytic residue at P172 (P = 0.0131);Loss of catalytic residue at P172 (P = 0.0131);

MVP

0.74

MPC

0.82

ClinPred

0.14

GERP RS

-5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.027

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over