Genetic Variant IGF2R:p.Arg18Leu (chr6-159969299-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000876.4(IGF2R):c.53G>T(p.Arg18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,239,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

IGF2R
NM_000876.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.171

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21794438).

BS2

High AC in GnomAd4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000876.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	NM_000876.4	MANE Select	c.53G>T	p.Arg18Leu	missense	Exon 1 of 48	NP_000867.3	P11717

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGF2R	ENST00000356956.6	TSL:1 MANE Select	c.53G>T	p.Arg18Leu	missense	Exon 1 of 48	ENSP00000349437.1	P11717
IGF2R	ENST00000676781.1		n.53G>T		non_coding_transcript_exon	Exon 1 of 49	ENSP00000504419.1	A0A7I2YQS7
IGF2R	ENST00000677704.1		n.53G>T		non_coding_transcript_exon	Exon 1 of 49	ENSP00000503314.1	A0A7I2V381

Frequencies

GnomAD3 genomes

AF:

0.000133

AC:

AN:

150172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

29838

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1088970

Hom.:

Cov.:

AF XY:

0.0000133

AC XY:

AN XY:

524348

show subpopulations

African (AFR)

AF:

0.000182

AC:

AN:

22022

American (AMR)

AF:

0.00

AC:

AN:

11984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15096

East Asian (EAS)

AF:

0.00

AC:

AN:

23000

South Asian (SAS)

AF:

0.00

AC:

AN:

29196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2930

European-Non Finnish (NFE)

AF:

0.0000163

AC:

AN:

921058

Other (OTH)

AF:

0.0000235

AC:

AN:

42466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000133

AC:

AN:

150280

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

73398

show subpopulations

African (AFR)

AF:

0.000484

AC:

AN:

41292

American (AMR)

AF:

0.00

AC:

AN:

15104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67384

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.0000434

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.13

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.98

PhyloP100

0.17

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.77

REVEL

Benign

0.075

Sift

Benign

0.15

Sift4G

Uncertain

0.054

Polyphen

0.98

Vest4

0.21

MutPred

0.23

Loss of MoRF binding (P = 0.0598)

MVP

0.35

MPC

0.11

ClinPred

0.54

GERP RS

2.1

PromoterAI

-0.052

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.10

gMVP

0.54

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over