dbSNP rs6413491: IGF2R:p.Ala724Thr (chr6-160047277-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000876.4(IGF2R):c.2170G>A(p.Ala724Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,612,466 control chromosomes in the GnomAD database, including 52 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 0.0094 ( 30 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 22 hom. )

Consequence

IGF2R
NM_000876.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.678

Publications

12 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044843554).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00936 (1424/152178) while in subpopulation AFR AF = 0.0318 (1321/41524). AF 95% confidence interval is 0.0304. There are 30 homozygotes in GnomAd4. There are 694 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1424 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2R	NM_000876.4 link	c.2170G>A	p.Ala724Thr	missense_variant	Exon 16 of 48	ENST00000356956.6	NP_000867.3	P11717

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGF2R	ENST00000356956.6 link	c.2170G>A	p.Ala724Thr	missense_variant	Exon 16 of 48	1	NM_000876.4	ENSP00000349437.1	P11717
IGF2R	ENST00000676781.1 link	n.*278G>A		non_coding_transcript_exon_variant	Exon 17 of 49			ENSP00000504419.1	A0A7I2YQS7
IGF2R	ENST00000677704.1 link	n.2170G>A		non_coding_transcript_exon_variant	Exon 16 of 49			ENSP00000503314.1	A0A7I2V381
IGF2R	ENST00000676781.1 link	n.*278G>A		3_prime_UTR_variant	Exon 17 of 49			ENSP00000504419.1	A0A7I2YQS7

Frequencies

GnomAD3 genomes

AF:

0.00935

AC:

1422

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00262

AC:

653

AN:

249584

AF XY:

0.00199

show subpopulations

Gnomad AFR exome

AF:

0.0337

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000221

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.00109

AC:

1588

AN:

1460288

Hom.:

Cov.:

AF XY:

0.000917

AC XY:

666

AN XY:

726500

show subpopulations

African (AFR)

AF:

0.0349

AC:

1165

AN:

33406

American (AMR)

AF:

0.00217

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52488

Middle Eastern (MID)

AF:

0.00607

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000127

AC:

141

AN:

1111688

Other (OTH)

AF:

0.00240

AC:

145

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

138

207

276

345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00936

AC:

1424

AN:

152178

Hom.:

Cov.:

AF XY:

0.00933

AC XY:

694

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0318

AC:

1321

AN:

41524

American (AMR)

AF:

0.00425

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

67966

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

122

183

244

305

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:

0.00331

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0313

AC:

138

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00312

AC:

379

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.098

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.85

.;T

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.91

PhyloP100

0.68

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.45

N;.

REVEL

Benign

0.029

Sift

Benign

0.17

T;.

Sift4G

Benign

0.25

T;.

Polyphen

0.071

B;B

Vest4

0.12

MVP

0.15

MPC

0.097

ClinPred

0.0014

GERP RS

1.5

Varity_R

0.058

gMVP

0.34

Mutation Taster

=91/9

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over