rs1570070

chr6-160032946-A-G

Variant summary

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

The NM_000876.4(IGF2R):c.1050A>G(p.Ser350=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,577,878 control chromosomes in the GnomAD database, including 99,156 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 0.33 (8942 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90214 hom.)
• Consequence: IGF2R NM_000876.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.107

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=-0.9).
• BP7: Synonymous conserved (PhyloP=-0.107 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2R	NM_000876.4	c.1050A>G	p.Ser350=	synonymous_variant	9/48	ENST00000356956.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2R	ENST00000356956.6	c.1050A>G	p.Ser350=	synonymous_variant	9/48	1	NM_000876.4	P1
IGF2R	ENST00000649737.1	n.287A>G		non_coding_transcript_exon_variant	2/3
IGF2R	ENST00000677704.1	c.1050A>G	p.Ser350=	synonymous_variant, NMD_transcript_variant	9/49
IGF2R	ENST00000676781.1	c.1050A>G	p.Ser350=	synonymous_variant, NMD_transcript_variant	9/49

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50237 AN: 151972 Hom.: 8941 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.334

GnomAD3 exomes AF: 0.379 AC: 94554 AN: 249624 Hom.: 19782 AF XY: 0.378 AC XY: 51032 AN XY: 135078

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.444

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.744

Gnomad SAS exome AF: 0.407

Gnomad FIN exome AF: 0.323

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.346 AC: 492965 AN: 1425788 Hom.: 90214 Cov.: 29 AF XY: 0.348 AC XY: 247170 AN XY: 711208

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.435

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.741

Gnomad4 SAS exome AF: 0.405

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.330 AC: 50249 AN: 152090 Hom.: 8942 Cov.: 32 AF XY: 0.334 AC XY: 24837 AN XY: 74344

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.746

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.312

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.339

Alfa AF: 0.337 Hom.: 12181

Bravo AF: 0.333

Asia WGS AF: 0.579 AC: 2015 AN: 3478

EpiCase AF: 0.329

EpiControl AF: 0.329

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.3
Dann	Benign	0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1570070; hg19: chr6-160453978; COSMIC: COSV63627556;