Genetic Variant IGF2R:p.Leu2222Leu (chr6-160096449-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000876.4(IGF2R):c.6666C>T(p.Leu2222Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0956 in 1,609,300 control chromosomes in the GnomAD database, including 13,537 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 2320 hom., cov: 33)

Exomes 𝑓: 0.091 ( 11217 hom. )

Consequence

IGF2R
NM_000876.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.154

Publications

31 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:

CHP1P2 (HGNC:54896): (CHP1 pseudogene 2) This locus on chromosome 6q25.3 represents a single-exon transcribed pseudogene of the multi-exon calcium binding protein P22 gene which resides on chromosome 15q13.3. This pseudogene is situated within an intron region of the insulin-like growth factor 2 receptor gene (IGF2R). [provided by RefSeq, Jan 2009]

CHP1P2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2R	NM_000876.4 link	c.6666C>T	p.Leu2222Leu	synonymous_variant	Exon 45 of 48	ENST00000356956.6	NP_000867.3	P11717
CHP1P2	NR_003288.2 link	n.*237C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6 link	c.6666C>T	p.Leu2222Leu	synonymous_variant	Exon 45 of 48	1	NM_000876.4	ENSP00000349437.1		P11717

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21551

AN:

152036

Hom.:

2304

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.412

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.0765

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0655

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.150

AC:

37338

AN:

248114

AF XY:

0.141

show subpopulations

Gnomad AFR exome

AF:

0.242

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.416

Gnomad FIN exome

AF:

0.0846

Gnomad NFE exome

AF:

0.0643

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.0908

AC:

132317

AN:

1457146

Hom.:

11217

Cov.:

AF XY:

0.0921

AC XY:

66721

AN XY:

724536

show subpopulations

African (AFR)

AF:

0.243

AC:

8087

AN:

33348

American (AMR)

AF:

0.296

AC:

13092

AN:

44208

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

288

AN:

26062

East Asian (EAS)

AF:

0.424

AC:

16714

AN:

39436

South Asian (SAS)

AF:

0.186

AC:

15915

AN:

85420

European-Finnish (FIN)

AF:

0.0840

AC:

4481

AN:

53374

Middle Eastern (MID)

AF:

0.0560

AC:

322

AN:

5750

European-Non Finnish (NFE)

AF:

0.0608

AC:

67462

AN:

1109304

Other (OTH)

AF:

0.0989

AC:

5956

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

4876

9751

14627

19502

24378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2926

5852

8778

11704

14630

<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:

0.142

AC:

21603

AN:

152154

Hom.:

2320

Cov.:

AF XY:

0.145

AC XY:

10806

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.239

AC:

9926

AN:

41468

American (AMR)

AF:

0.197

AC:

3015

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.412

AC:

2127

AN:

5168

South Asian (SAS)

AF:

0.188

AC:

905

AN:

4820

European-Finnish (FIN)

AF:

0.0765

AC:

811

AN:

10596

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0655

AC:

4454

AN:

68024

Other (OTH)

AF:

0.133

AC:

280

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

902

1804

2706

3608

4510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<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:

0.0937

Hom.:

4741

Bravo

AF:

0.156

Asia WGS

AF:

0.305

AC:

1061

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

1.5

(source)

DANN

Benign

0.87

PhyloP100

-0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=88/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: 28

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over