Genetic Variant IGF2R:p.Arg18Ser (chr6-159969298-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000876.4(IGF2R):c.52C>A(p.Arg18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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. R18L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IGF2R
NM_000876.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.737

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23064733).

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.52C>A	p.Arg18Ser	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.52C>A	p.Arg18Ser	missense	Exon 1 of 48	ENSP00000349437.1	P11717
IGF2R	ENST00000676781.1		n.52C>A		non_coding_transcript_exon	Exon 1 of 49	ENSP00000504419.1	A0A7I2YQS7
IGF2R	ENST00000677704.1		n.52C>A		non_coding_transcript_exon	Exon 1 of 49	ENSP00000503314.1	A0A7I2V381

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

28816

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1088964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

524078

African (AFR)

AF:

0.00

AC:

AN:

22048

American (AMR)

AF:

0.00

AC:

AN:

11930

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15044

East Asian (EAS)

AF:

0.00

AC:

AN:

23120

South Asian (SAS)

AF:

0.00

AC:

AN:

28882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2922

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

921246

Other (OTH)

AF:

0.00

AC:

AN:

42538

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.48

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.99

PhyloP100

-0.74

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.27

REVEL

Benign

0.078

Sift

Benign

0.13

Sift4G

Uncertain

0.045

Polyphen

0.98

Vest4

0.16

MutPred

0.19

Gain of phosphorylation at R18 (P = 0.0166)

MVP

0.28

MPC

0.10

ClinPred

0.44

GERP RS

2.1

PromoterAI

-0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.15

gMVP

0.60

Mutation Taster

=86/14

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over