Genetic Variant IGF2R:p.Arg1619Gly (chr6-160073377-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000876.4(IGF2R):c.4855A>G(p.Arg1619Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,614,202 control chromosomes in the GnomAD database, including 629,117 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.91 ( 63506 hom., cov: 35)

Exomes 𝑓: 0.88 ( 565611 hom. )

Consequence

IGF2R
NM_000876.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

Publications

72 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

new If you want to explore the variant's impact on the transcript NM_000876.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.4388586E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

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.4855A>G	p.Arg1619Gly	missense	Exon 34 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.4855A>G	p.Arg1619Gly	missense	Exon 34 of 48	ENSP00000349437.1	P11717
IGF2R	ENST00000650503.1		n.1465A>G		non_coding_transcript_exon	Exon 11 of 24
IGF2R	ENST00000676781.1		n.*2963A>G		non_coding_transcript_exon	Exon 35 of 49	ENSP00000504419.1	A0A7I2YQS7

Frequencies

GnomAD3 genomes

AF:

0.912

AC:

138820

AN:

152232

Hom.:

63442

Cov.:

show subpopulations

Gnomad AFR

AF:

0.975

Gnomad AMI

AF:

0.910

Gnomad AMR

AF:

0.913

Gnomad ASJ

AF:

0.951

Gnomad EAS

AF:

0.830

Gnomad SAS

AF:

0.889

Gnomad FIN

AF:

0.916

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.878

Gnomad OTH

AF:

0.909

GnomAD2 exomes

AF:

0.899

AC:

225927

AN:

251418

AF XY:

0.896

show subpopulations

Gnomad AFR exome

AF:

0.977

Gnomad AMR exome

AF:

0.942

Gnomad ASJ exome

AF:

0.949

Gnomad EAS exome

AF:

0.839

Gnomad FIN exome

AF:

0.908

Gnomad NFE exome

AF:

0.877

Gnomad OTH exome

AF:

0.900

GnomAD4 exome

AF:

0.879

AC:

1285017

AN:

1461852

Hom.:

565611

Cov.:

AF XY:

0.880

AC XY:

640053

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.981

AC:

32836

AN:

33480

American (AMR)

AF:

0.939

AC:

41997

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.946

AC:

24716

AN:

26136

East Asian (EAS)

AF:

0.832

AC:

33046

AN:

39698

South Asian (SAS)

AF:

0.901

AC:

77748

AN:

86258

European-Finnish (FIN)

AF:

0.908

AC:

48484

AN:

53420

Middle Eastern (MID)

AF:

0.951

AC:

5484

AN:

5768

European-Non Finnish (NFE)

AF:

0.870

AC:

966962

AN:

1111974

Other (OTH)

AF:

0.890

AC:

53744

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

9008

18016

27024

36032

45040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21290

42580

63870

85160

106450

<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:

0.912

AC:

138943

AN:

152350

Hom.:

63506

Cov.:

AF XY:

0.912

AC XY:

67937

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.975

AC:

40559

AN:

41594

American (AMR)

AF:

0.914

AC:

13986

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.951

AC:

3302

AN:

3472

East Asian (EAS)

AF:

0.831

AC:

4289

AN:

5164

South Asian (SAS)

AF:

0.889

AC:

4295

AN:

4832

European-Finnish (FIN)

AF:

0.916

AC:

9734

AN:

10624

Middle Eastern (MID)

AF:

0.966

AC:

284

AN:

294

European-Non Finnish (NFE)

AF:

0.878

AC:

59744

AN:

68036

Other (OTH)

AF:

0.909

AC:

1922

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

663

1325

1988

2650

3313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.893

Hom.:

193283

Bravo

AF:

0.916

Asia WGS

AF:

0.878

AC:

3053

AN:

3478

EpiCase

AF:

0.884

EpiControl

AF:

0.882

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.052

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.12

MetaRNN

Benign

8.4e-7

MetaSVM

Benign

-0.94

PhyloP100

2.0

PrimateAI

Benign

0.30

PROVEAN

Benign

3.6

REVEL

Benign

0.087

Sift

Benign

1.0

Sift4G

Benign

1.0

Varity_R

0.056

gMVP

0.70

Mutation Taster

=93/7

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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