Variant rs8191754 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000876.4(IGF2R):c.754C>G(p.Leu252Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,260 control chromosomes in the GnomAD database, including 15,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.13 ( 1350 hom., cov: 33)

Exomes 𝑓: 0.14 ( 14351 hom. )

Consequence

IGF2R
NM_000876.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.96

Variant links:

Genes affected

IGF2R (HGNC:5467): (insulin like growth factor 2 receptor) This gene encodes a receptor for both insulin-like growth factor 2 and mannose 6-phosphate. The binding sites for each ligand are located on different segments of the protein. This receptor has various functions, including in the intracellular trafficking of lysosomal enzymes, the activation of transforming growth factor beta, and the degradation of insulin-like growth factor 2. Mutation or loss of heterozygosity of this gene has been association with risk of hepatocellular carcinoma. The orthologous mouse gene is imprinted and shows exclusive expression from the maternal allele; however, imprinting of the human gene may be polymorphic, as only a minority of individuals showed biased expression from the maternal allele (PMID:8267611). [provided by RefSeq, Nov 2015]

IGF2R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017426014).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4 linkuse as main transcript	c.754C>G	p.Leu252Val	missense_variant	6/48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
IGF2R	ENST00000356956.6 linkuse as main transcript	c.754C>G	p.Leu252Val	missense_variant	6/48	1	NM_000876.4	ENSP00000349437	P1
IGF2R	ENST00000677704.1 linkuse as main transcript	c.754C>G	p.Leu252Val	missense_variant, NMD_transcript_variant	6/49			ENSP00000503314
IGF2R	ENST00000676781.1 linkuse as main transcript	c.754C>G	p.Leu252Val	missense_variant, NMD_transcript_variant	6/49			ENSP00000504419

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20154

AN:

152168

Hom.:

1352

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.0920

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.0960

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.133

AC:

33205

AN:

249804

Hom.:

2396

AF XY:

0.137

AC XY:

18491

AN XY:

135092

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.0686

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.223

Gnomad SAS exome

AF:

0.173

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.134

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.138

AC:

201301

AN:

1460974

Hom.:

14351

Cov.:

AF XY:

0.139

AC XY:

101218

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.0729

Gnomad4 ASJ exome

AF:

0.115

Gnomad4 EAS exome

AF:

0.231

Gnomad4 SAS exome

AF:

0.178

Gnomad4 FIN exome

AF:

0.106

Gnomad4 NFE exome

AF:

0.136

Gnomad4 OTH exome

AF:

0.139

GnomAD4 genome

AF:

0.132

AC:

20147

AN:

152286

Hom.:

1350

Cov.:

AF XY:

0.130

AC XY:

9700

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.0917

Gnomad4 ASJ

AF:

0.123

Gnomad4 EAS

AF:

0.222

Gnomad4 SAS

AF:

0.191

Gnomad4 FIN

AF:

0.0960

Gnomad4 NFE

AF:

0.133

Gnomad4 OTH

AF:

0.128

Alfa

AF:

0.137

Hom.:

1109

Bravo

AF:

0.130

TwinsUK

AF:

0.141

AC:

523

ALSPAC

AF:

0.140

AC:

540

ESP6500AA

AF:

0.139

AC:

614

ESP6500EA

AF:

0.131

AC:

1126

ExAC

AF:

0.135

AC:

16397

Asia WGS

AF:

0.202

AC:

703

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

.;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.2

MutationTaster

Benign

0.00012

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.18

Sift

Uncertain

0.019

D;.

Sift4G

Uncertain

0.0090

D;.

Polyphen

0.87

P;P

Vest4

0.17

MPC

0.48

ClinPred

0.030

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.70

gMVP

0.59

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over