rs2274849

chr6-160058850-G-Achr6-160058850-G-C

Variant summary

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

The NM_000876.4(IGF2R):c.2899-56G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,471,852 control chromosomes in the GnomAD database, including 41,438 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 0.26 (5295 hom., cov: 32)
  • Exomes 𝑓: 0.23 (36143 hom.)
• Consequence: IGF2R NM_000876.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2R	NM_000876.4	c.2899-56G>A		intron_variant		ENST00000356956.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2R	ENST00000356956.6	c.2899-56G>A		intron_variant		1	NM_000876.4	P1
IGF2R	ENST00000676781.1	c.*1007-56G>A		intron_variant, NMD_transcript_variant
IGF2R	ENST00000677704.1	c.2899-56G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39353 AN: 151982 Hom.: 5282 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.241

GnomAD4 exome AF: 0.231 AC: 304271 AN: 1319752 Hom.: 36143 AF XY: 0.229 AC XY: 151093 AN XY: 659498

Gnomad4 AFR exome AF: 0.325

Gnomad4 AMR exome AF: 0.339

Gnomad4 ASJ exome AF: 0.162

Gnomad4 EAS exome AF: 0.316

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.223

Gnomad4 OTH exome AF: 0.230

GnomAD4 genome AF: 0.259 AC: 39406 AN: 152100 Hom.: 5295 Cov.: 32 AF XY: 0.258 AC XY: 19180 AN XY: 74366

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.272

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.204

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.244

Alfa AF: 0.236 Hom.: 7108

Bravo AF: 0.270

Asia WGS AF: 0.296 AC: 1032 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.86
Dann	Benign	0.58
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: rs2274849; hg19: chr6-160479882; COSMIC: COSV63629437;