chr11-2147784-A-G

Variant names:

Variant summary

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

The ENST00000397270.1(INS-IGF2):c.431T>C(p.Leu144Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,247,656 control chromosomes in the GnomAD database, including 137,657 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 0.40 ( 14052 hom., cov: 31)

Exomes 𝑓: 0.47 ( 123605 hom. )

Consequence

INS-IGF2
ENST00000397270.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.489

Publications

44 publications found

Variant links:

Genes affected

INS-IGF2 (HGNC:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

INS-IGF2 links:

ENSG00000284779 (HGNC:):

ENSG00000284779 links:

IGF2 (HGNC:5466): (insulin like growth factor 2) This gene encodes a member of the insulin family of polypeptide growth factors, which are involved in development and growth. It is an imprinted gene, expressed only from the paternal allele, and epigenetic changes at this locus are associated with Wilms tumour, Beckwith-Wiedemann syndrome, rhabdomyosarcoma, and Silver-Russell syndrome. A read-through INS-IGF2 gene exists, whose 5' region overlaps the INS gene and the 3' region overlaps this gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

IGF2 links:

IGF2-AS (HGNC:14062): (IGF2 antisense RNA) This gene is expressed in antisense to the insulin-like growth factor 2 (IGF2) gene and is imprinted and paternally expressed. It is thought to be non-coding because the putative protein is not conserved and translation is predicted to trigger nonsense mediated decay (NMD). Transcripts from this gene are produced in tumors and may function to suppress cell growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

IGF2-AS 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=2.988811E-5).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
IGF2	NM_001007139.6 link	c.-225T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 5	NP_001007140.2	P01344-1
INS-IGF2	NM_001042376.3 link	c.431T>C	p.Leu144Pro	missense_variant	Exon 4 of 5	NP_001035835.1	F8WCM5-1
INS-IGF2	NR_003512.4 link	n.490T>C		non_coding_transcript_exon_variant	Exon 4 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS-IGF2	ENST00000397270.1 link	c.431T>C	p.Leu144Pro	missense_variant	Exon 4 of 5	1		ENSP00000380440.1		F8WCM5-1
ENSG00000284779	ENST00000643349.2 link	c.278T>C	p.Leu93Pro	missense_variant	Exon 2 of 5			ENSP00000495715.1		A0A2R8Y747

Frequencies

GnomAD3 genomes

AF:

0.403

AC:

61133

AN:

151726

Hom.:

14036

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.622

Gnomad AMR

AF:

0.538

Gnomad ASJ

AF:

0.462

Gnomad EAS

AF:

0.375

Gnomad SAS

AF:

0.348

Gnomad FIN

AF:

0.563

Gnomad MID

AF:

0.401

Gnomad NFE

AF:

0.485

Gnomad OTH

AF:

0.417

GnomAD2 exomes

AF:

0.491

AC:

11376

AN:

23166

AF XY:

0.503

show subpopulations

Gnomad AFR exome

AF:

0.175

Gnomad AMR exome

AF:

0.582

Gnomad ASJ exome

AF:

0.483

Gnomad EAS exome

AF:

0.400

Gnomad FIN exome

AF:

0.583

Gnomad NFE exome

AF:

0.474

Gnomad OTH exome

AF:

0.460

GnomAD4 exome

AF:

0.471

AC:

515905

AN:

1095808

Hom.:

123605

Cov.:

AF XY:

0.470

AC XY:

243404

AN XY:

517460

show subpopulations

African (AFR)

AF:

0.161

AC:

3710

AN:

23042

American (AMR)

AF:

0.574

AC:

4838

AN:

8434

Ashkenazi Jewish (ASJ)

AF:

0.452

AC:

6500

AN:

14392

East Asian (EAS)

AF:

0.467

AC:

12389

AN:

26542

South Asian (SAS)

AF:

0.353

AC:

6931

AN:

19654

European-Finnish (FIN)

AF:

0.574

AC:

20240

AN:

35272

Middle Eastern (MID)

AF:

0.446

AC:

1953

AN:

4380

European-Non Finnish (NFE)

AF:

0.478

AC:

440184

AN:

920162

Other (OTH)

AF:

0.436

AC:

19160

AN:

43930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

14315

28630

42945

57260

71575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14938

29876

44814

59752

74690

<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:

0.403

AC:

61163

AN:

151848

Hom.:

14052

Cov.:

AF XY:

0.409

AC XY:

30329

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.177

AC:

7331

AN:

41430

American (AMR)

AF:

0.539

AC:

8230

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

1603

AN:

3468

East Asian (EAS)

AF:

0.376

AC:

1921

AN:

5110

South Asian (SAS)

AF:

0.348

AC:

1676

AN:

4816

European-Finnish (FIN)

AF:

0.563

AC:

5942

AN:

10554

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.485

AC:

32901

AN:

67884

Other (OTH)

AF:

0.417

AC:

879

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1629

3257

4886

6514

8143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

574

1148

1722

2296

2870

<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:

0.458

Hom.:

62789

Bravo

AF:

0.392

TwinsUK

AF:

0.482

AC:

1787

ALSPAC

AF:

0.475

AC:

1831

ESP6500AA

AF:

0.167

AC:

560

ESP6500EA

AF:

0.430

AC:

3133

ExAC

AF:

0.276

AC:

10533

Asia WGS

AF:

0.359

AC:

1247

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.34

T;T

MetaRNN

Benign

0.000030

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;N

PhyloP100

0.49

PROVEAN

Benign

-0.65

.;N

REVEL

Benign

0.19

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

0.36

.;B

Vest4

0.16

MPC

1.2

ClinPred

0.045

GERP RS

1.1

Varity_R

0.25

gMVP

0.47

Mutation Taster

=97/3

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

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