chr6-160058850-G-A

Variant names:

• chr6-160058850-G-A
• rs2274849
• NM_000876.4:c.2899-56G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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 -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 rank	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.2899-56G>A		intron_variant	Intron 21 of 47	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.2899-56G>A		intron_variant	Intron 21 of 47	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000676781.1	n.*1007-56G>A		intron_variant	Intron 22 of 48			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.2899-56G>A		intron_variant	Intron 21 of 48			ENSP00000503314.1

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

African (AFR) AF: 0.325 AC: 9781 AN: 30090

American (AMR) AF: 0.339 AC: 14034 AN: 41396

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 3886 AN: 23926

East Asian (EAS) AF: 0.316 AC: 12229 AN: 38646

South Asian (SAS) AF: 0.221 AC: 17948 AN: 81226

European-Finnish (FIN) AF: 0.229 AC: 12037 AN: 52574

Middle Eastern (MID) AF: 0.175 AC: 945 AN: 5394

European-Non Finnish (NFE) AF: 0.223 AC: 220682 AN: 991258

Other (OTH) AF: 0.230 AC: 12729 AN: 55242

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

African (AFR) AF: 0.323 AC: 13404 AN: 41462

American (AMR) AF: 0.272 AC: 4156 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3468

East Asian (EAS) AF: 0.330 AC: 1707 AN: 5170

South Asian (SAS) AF: 0.204 AC: 985 AN: 4826

European-Finnish (FIN) AF: 0.224 AC: 2370 AN: 10598

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15481 AN: 67984

Other (OTH) AF: 0.244 AC: 516 AN: 2114

Alfa AF: 0.239 Hom.: 11152

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
PhyloP100		0.096
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs2274849; hg19: chr6-160479882; COSMIC: COSV63629437;