6-160048478-C-G

Position:

chr6-160048478-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000356956.6(IGF2R):c.2449C>G(p.Leu817Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,614,220 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0059 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 115 hom. )

Consequence

IGF2R
ENST00000356956.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.42

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005435288).

BP6

Variant 6-160048478-C-G is Benign according to our data. Variant chr6-160048478-C-G is described in ClinVar as [Benign]. Clinvar id is 771868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0059 (899/152382) while in subpopulation SAS AF= 0.0215 (104/4834). AF 95% confidence interval is 0.0182. There are 8 homozygotes in gnomad4. There are 439 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 899 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4 linkuse as main transcript	c.2449C>G	p.Leu817Val	missense_variant	18/48	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.2449C>G	p.Leu817Val	missense_variant	18/48	1	NM_000876.4	ENSP00000349437	P1
IGF2R	ENST00000677704.1 linkuse as main transcript	c.2449C>G	p.Leu817Val	missense_variant, NMD_transcript_variant	18/49			ENSP00000503314
IGF2R	ENST00000676781.1 linkuse as main transcript	c.*557C>G		3_prime_UTR_variant, NMD_transcript_variant	19/49			ENSP00000504419

Frequencies

GnomAD3 genomes

AF:

0.00592

AC:

901

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.00611

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.00692

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00955

AC:

2401

AN:

251456

Hom.:

AF XY:

0.0109

AC XY:

1481

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00558

Gnomad ASJ exome

AF:

0.0302

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0252

Gnomad FIN exome

AF:

0.00582

Gnomad NFE exome

AF:

0.00805

Gnomad OTH exome

AF:

0.0125

GnomAD4 exome

AF:

0.00722

AC:

10548

AN:

1461838

Hom.:

115

Cov.:

AF XY:

0.00799

AC XY:

5814

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00586

Gnomad4 ASJ exome

AF:

0.0307

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0237

Gnomad4 FIN exome

AF:

0.00584

Gnomad4 NFE exome

AF:

0.00564

Gnomad4 OTH exome

AF:

0.00984

GnomAD4 genome

AF:

0.00590

AC:

899

AN:

152382

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

439

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00503

Gnomad4 ASJ

AF:

0.0288

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0215

Gnomad4 FIN

AF:

0.00611

Gnomad4 NFE

AF:

0.00692

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00863

Hom.:

Bravo

AF:

0.00559

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00849

AC:

ExAC

AF:

0.00938

AC:

1139

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.0111

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	IGF2R: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

.;D

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.13

Sift

Benign

0.088

T;.

Sift4G

Uncertain

0.012

D;.

Polyphen

0.98

D;D

Vest4

0.53

MVP

0.39

MPC

0.45

ClinPred

0.023

GERP RS

4.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.13

gMVP

0.62

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over