rs1805075

Positions:

• chr6-160084175-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000876.4(IGF2R):​c.6059A>G​(p.Asn2020Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0618 in 1,608,400 control chromosomes in the GnomAD database, including 6,251 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.061 (639 hom., cov: 32)
  • Exomes 𝑓: 0.062 (5612 hom.)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046558976).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.6059A>G	p.Asn2020Ser	missense_variant	40/48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.6059A>G	p.Asn2020Ser	missense_variant	40/48	1	NM_000876.4	ENSP00000349437.1

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 9208 AN: 152032 Hom.: 634 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0689

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0559

GnomAD3 exomes AF: 0.104 AC: 26079 AN: 250810 Hom.: 2735 AF XY: 0.0974 AC XY: 13213 AN XY: 135650

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.00795

Gnomad EAS exome AF: 0.325

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.0757

Gnomad NFE exome AF: 0.0475

Gnomad OTH exome AF: 0.0756

GnomAD4 exome AF: 0.0620 AC: 90248 AN: 1456250 Hom.: 5612 Cov.: 30 AF XY: 0.0624 AC XY: 45214 AN XY: 724766

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.246

Gnomad4 ASJ exome AF: 0.00808

Gnomad4 EAS exome AF: 0.315

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.0749

Gnomad4 NFE exome AF: 0.0443

Gnomad4 OTH exome AF: 0.0608

GnomAD4 genome AF: 0.0606 AC: 9216 AN: 152150 Hom.: 639 Cov.: 32 AF XY: 0.0643 AC XY: 4779 AN XY: 74372

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0689

Gnomad4 NFE AF: 0.0495

Gnomad4 OTH AF: 0.0610

Alfa AF: 0.0525 Hom.: 898

Bravo AF: 0.0673

TwinsUK AF: 0.0394 AC: 146

ALSPAC AF: 0.0451 AC: 174

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.0417 AC: 359

ExAC AF: 0.0973 AC: 11807

Asia WGS AF: 0.215 AC: 750 AN: 3478

EpiCase AF: 0.0403

EpiControl AF: 0.0383

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.71
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.39	.;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.39	N;.
REVEL	Benign	0.11
Sift	Benign	0.23	T;.
Sift4G	Benign	0.45	T;.
Polyphen		0.0	B;B
Vest4		0.022
MPC		0.32
ClinPred		0.012	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs1805075; hg19: chr6-160505207; COSMIC: COSV63626927; COSMIC: COSV63626927;