chr6-160047246-A-G

Position:

• chr6-160047246-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.2139A>G​(p.Thr713=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,613,148 control chromosomes in the GnomAD database, including 201,686 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 0.54 (22251 hom., cov: 32)
  • Exomes 𝑓: 0.49 (179435 hom.)
• Consequence: IGF2R NM_000876.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56

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=-0.82).
• BP7: Synonymous conserved (PhyloP=-1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.2139A>G	p.Thr713=	synonymous_variant	16/48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.2139A>G	p.Thr713=	synonymous_variant	16/48	1	NM_000876.4	ENSP00000349437	P1
IGF2R	ENST00000677704.1	c.2139A>G	p.Thr713=	synonymous_variant, NMD_transcript_variant	16/49			ENSP00000503314
IGF2R	ENST00000676781.1	c.*247A>G		3_prime_UTR_variant, NMD_transcript_variant	17/49			ENSP00000504419

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81586 AN: 151902 Hom.: 22208 Cov.: 32

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.537

GnomAD3 exomes AF: 0.530 AC: 133034 AN: 250996 Hom.: 35830 AF XY: 0.528 AC XY: 71591 AN XY: 135666

Gnomad AFR exome AF: 0.623

Gnomad AMR exome AF: 0.541

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.673

Gnomad SAS exome AF: 0.535

Gnomad FIN exome AF: 0.590

Gnomad NFE exome AF: 0.485

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.493 AC: 720258 AN: 1461128 Hom.: 179435 Cov.: 38 AF XY: 0.494 AC XY: 359134 AN XY: 726900

Gnomad4 AFR exome AF: 0.623

Gnomad4 AMR exome AF: 0.539

Gnomad4 ASJ exome AF: 0.452

Gnomad4 EAS exome AF: 0.670

Gnomad4 SAS exome AF: 0.535

Gnomad4 FIN exome AF: 0.581

Gnomad4 NFE exome AF: 0.473

Gnomad4 OTH exome AF: 0.508

GnomAD4 genome AF: 0.537 AC: 81681 AN: 152020 Hom.: 22251 Cov.: 32 AF XY: 0.541 AC XY: 40216 AN XY: 74304

Gnomad4 AFR AF: 0.616

Gnomad4 AMR AF: 0.512

Gnomad4 ASJ AF: 0.451

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.528

Gnomad4 FIN AF: 0.590

Gnomad4 NFE AF: 0.482

Gnomad4 OTH AF: 0.542

Alfa AF: 0.492 Hom.: 27715

Bravo AF: 0.537

Asia WGS AF: 0.628 AC: 2185 AN: 3478

EpiCase AF: 0.497

EpiControl AF: 0.496

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.039
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs998075; hg19: chr6-160468278; COSMIC: COSV63634177;