rs894817

Positions:

• chr6-160043257-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000876.4(IGF2R):​c.1590G>A​(p.Gly530=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,798 control chromosomes in the GnomAD database, including 95,465 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 0.32 (8485 hom., cov: 33)
  • Exomes 𝑓: 0.34 (86980 hom.)
• Consequence: IGF2R NM_000876.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.628

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=0.628 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.1590G>A	p.Gly530=	synonymous_variant	12/48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.1590G>A	p.Gly530=	synonymous_variant	12/48	1	NM_000876.4	ENSP00000349437	P1
IGF2R	ENST00000677704.1	c.1590G>A	p.Gly530=	synonymous_variant, NMD_transcript_variant	12/49			ENSP00000503314
IGF2R	ENST00000676781.1	c.1590G>A	p.Gly530=	synonymous_variant, NMD_transcript_variant	12/49			ENSP00000504419

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48887 AN: 152052 Hom.: 8478 Cov.: 33

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.326

GnomAD3 exomes AF: 0.362 AC: 90935 AN: 251384 Hom.: 18488 AF XY: 0.359 AC XY: 48809 AN XY: 135860

Gnomad AFR exome AF: 0.273

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.743

Gnomad SAS exome AF: 0.385

Gnomad FIN exome AF: 0.268

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.335 AC: 489673 AN: 1461628 Hom.: 86980 Cov.: 36 AF XY: 0.336 AC XY: 244100 AN XY: 727112

Gnomad4 AFR exome AF: 0.269

Gnomad4 AMR exome AF: 0.428

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.740

Gnomad4 SAS exome AF: 0.386

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.320

Gnomad4 OTH exome AF: 0.340

GnomAD4 genome AF: 0.321 AC: 48904 AN: 152170 Hom.: 8485 Cov.: 33 AF XY: 0.323 AC XY: 24050 AN XY: 74394

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.370

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.747

Gnomad4 SAS AF: 0.407

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.332

Alfa AF: 0.321 Hom.: 11556

Bravo AF: 0.328

Asia WGS AF: 0.573 AC: 1994 AN: 3478

EpiCase AF: 0.312

EpiControl AF: 0.312

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.8
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs894817; hg19: chr6-160464289; COSMIC: COSV63627581;