6-160047246-A-G

Variant names:

• chr6-160047246-A-G
• rs998075
• NM_000876.4:c.2139A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000876.4(IGF2R):​c.2139A>G​(p.Thr713Thr) 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
• Publications: 43 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000876.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	NM_000876.4	MANE Select	c.2139A>G	p.Thr713Thr	synonymous	Exon 16 of 48	NP_000867.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	ENST00000356956.6	TSL:1 MANE Select	c.2139A>G	p.Thr713Thr	synonymous	Exon 16 of 48	ENSP00000349437.1
	IGF2R	ENST00000676781.1		n.*247A>G		non_coding_transcript_exon	Exon 17 of 49	ENSP00000504419.1
	IGF2R	ENST00000677704.1		n.2139A>G		non_coding_transcript_exon	Exon 16 of 49	ENSP00000503314.1

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

GnomAD2 exomes AF: 0.530 AC: 133034 AN: 250996 AF XY: 0.528

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 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

African (AFR) AF: 0.623 AC: 20857 AN: 33464

American (AMR) AF: 0.539 AC: 24113 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 11810 AN: 26124

East Asian (EAS) AF: 0.670 AC: 26603 AN: 39694

South Asian (SAS) AF: 0.535 AC: 46125 AN: 86252

European-Finnish (FIN) AF: 0.581 AC: 30852 AN: 53088

Middle Eastern (MID) AF: 0.554 AC: 3193 AN: 5766

European-Non Finnish (NFE) AF: 0.473 AC: 526053 AN: 1111656

Other (OTH) AF: 0.508 AC: 30652 AN: 60370

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

African (AFR) AF: 0.616 AC: 25550 AN: 41444

American (AMR) AF: 0.512 AC: 7829 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1567 AN: 3472

East Asian (EAS) AF: 0.671 AC: 3463 AN: 5164

South Asian (SAS) AF: 0.528 AC: 2538 AN: 4810

European-Finnish (FIN) AF: 0.590 AC: 6245 AN: 10576

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.482 AC: 32784 AN: 67960

Other (OTH) AF: 0.542 AC: 1144 AN: 2110

Alfa AF: 0.500 Hom.: 70980

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.039
DANN	Benign	0.31
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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