rs8191904

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000876.4(IGF2R):c.5495G>A(p.Arg1832His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,452,580 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0092 ( 25 hom., cov: 33)

Exomes 𝑓: 0.00086 ( 14 hom. )

Consequence

IGF2R
NM_000876.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0340

Publications

7 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029729903).

BP6

Variant 6-160079596-G-A is Benign according to our data. Variant chr6-160079596-G-A is described in ClinVar as Benign. ClinVar VariationId is 709060.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00923 (1406/152318) while in subpopulation AFR AF = 0.0319 (1325/41552). AF 95% confidence interval is 0.0305. There are 25 homozygotes in GnomAd4. There are 639 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1406 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	NM_000876.4	MANE Select	c.5495G>A	p.Arg1832His	missense	Exon 38 of 48	NP_000867.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IGF2R	ENST00000356956.6	TSL:1 MANE Select	c.5495G>A	p.Arg1832His	missense	Exon 38 of 48	ENSP00000349437.1
IGF2R	ENST00000650503.1		n.2105G>A		non_coding_transcript_exon	Exon 15 of 24
IGF2R	ENST00000676781.1		n.*3603G>A		non_coding_transcript_exon	Exon 39 of 49	ENSP00000504419.1

Frequencies

GnomAD3 genomes

AF:

0.00914

AC:

1391

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0316

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00255

AC:

396

AN:

155224

AF XY:

0.00186

show subpopulations

Gnomad AFR exome

AF:

0.0310

Gnomad AMR exome

AF:

0.00123

Gnomad ASJ exome

AF:

0.000229

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000755

Gnomad OTH exome

AF:

0.000319

GnomAD4 exome

AF:

0.000861

AC:

1120

AN:

1300262

Hom.:

Cov.:

AF XY:

0.000787

AC XY:

501

AN XY:

636640

show subpopulations

African (AFR)

AF:

0.0326

AC:

894

AN:

27424

American (AMR)

AF:

0.00185

AC:

AN:

22710

Ashkenazi Jewish (ASJ)

AF:

0.000305

AC:

AN:

19686

East Asian (EAS)

AF:

0.00

AC:

AN:

33278

South Asian (SAS)

AF:

0.0000331

AC:

AN:

60492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49062

Middle Eastern (MID)

AF:

0.00117

AC:

AN:

5110

European-Non Finnish (NFE)

AF:

0.0000641

AC:

AN:

1029664

Other (OTH)

AF:

0.00197

AC:

104

AN:

52836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00923

AC:

1406

AN:

152318

Hom.:

Cov.:

AF XY:

0.00858

AC XY:

639

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0319

AC:

1325

AN:

41552

American (AMR)

AF:

0.00366

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68034

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00746

Hom.:

768

Bravo

AF:

0.0104

ESP6500AA

AF:

0.0288

AC:

127

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00289

AC:

351

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.077

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.93

PhyloP100

0.034

PrimateAI

Benign

0.27

PROVEAN

Benign

0.13

REVEL

Benign

0.036

Sift

Benign

0.62

Sift4G

Benign

0.46

Polyphen

0.0020

Vest4

0.071

MVP

0.27

MPC

0.50

ClinPred

0.0064

GERP RS

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.40

Mutation Taster

=90/10

polymorphism

(source)

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over