Genetic Variant IGF2R:c.6656-2930T>C (chr6-160093509-T-C) – 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.6656-2930T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 575,932 control chromosomes in the GnomAD database, including 57,111 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 0.45 ( 16323 hom., cov: 32)

Exomes 𝑓: 0.43 ( 40788 hom. )

Consequence

IGF2R
NM_000876.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.943

Publications

10 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2R	NM_000876.4 link	c.6656-2930T>C		intron_variant	Intron 44 of 47	ENST00000356956.6	NP_000867.3	P11717
CHP1P2	NR_003288.2 link	n.428T>C		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6 link	c.6656-2930T>C		intron_variant	Intron 44 of 47	1	NM_000876.4	ENSP00000349437.1		P11717

Frequencies

GnomAD3 genomes

AF:

0.453

AC:

68727

AN:

151840

Hom.:

16281

Cov.:

show subpopulations

Gnomad AFR

AF:

0.576

Gnomad AMI

AF:

0.395

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.379

Gnomad EAS

AF:

0.674

Gnomad SAS

AF:

0.468

Gnomad FIN

AF:

0.359

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.380

Gnomad OTH

AF:

0.447

GnomAD4 exome

AF:

0.429

AC:

181807

AN:

423974

Hom.:

40788

Cov.:

AF XY:

0.429

AC XY:

99287

AN XY:

231204

show subpopulations

African (AFR)

AF:

0.587

AC:

6898

AN:

11746

American (AMR)

AF:

0.495

AC:

12242

AN:

24708

Ashkenazi Jewish (ASJ)

AF:

0.369

AC:

4114

AN:

11148

East Asian (EAS)

AF:

0.687

AC:

17694

AN:

25766

South Asian (SAS)

AF:

0.478

AC:

25011

AN:

52304

European-Finnish (FIN)

AF:

0.367

AC:

12109

AN:

32962

Middle Eastern (MID)

AF:

0.487

AC:

1230

AN:

2526

European-Non Finnish (NFE)

AF:

0.387

AC:

93124

AN:

240692

Other (OTH)

AF:

0.424

AC:

9385

AN:

22122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

4897

9794

14690

19587

24484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.453

AC:

68816

AN:

151958

Hom.:

16323

Cov.:

AF XY:

0.452

AC XY:

33611

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.577

AC:

23890

AN:

41414

American (AMR)

AF:

0.446

AC:

6813

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

1315

AN:

3466

East Asian (EAS)

AF:

0.674

AC:

3473

AN:

5154

South Asian (SAS)

AF:

0.468

AC:

2249

AN:

4810

European-Finnish (FIN)

AF:

0.359

AC:

3801

AN:

10578

Middle Eastern (MID)

AF:

0.517

AC:

152

AN:

294

European-Non Finnish (NFE)

AF:

0.380

AC:

25807

AN:

67948

Other (OTH)

AF:

0.453

AC:

957

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1873

3746

5619

7492

9365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.417

Hom.:

37271

Bravo

AF:

0.468

Asia WGS

AF:

0.600

AC:

2086

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.8

(source)

DANN

Benign

0.62

PhyloP100

-0.94

Mutation Taster

=100/0

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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chr6-160093509-T-C

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