NM_000876.4:c.6666C>T

Variant names:

• chr6-160096449-C-T
• rs1803989
• NM_000876.4:c.6666C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000876.4(IGF2R):​c.6666C>T​(p.Leu2222Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0956 in 1,609,300 control chromosomes in the GnomAD database, including 13,537 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 0.14 (2320 hom., cov: 33)
  • Exomes 𝑓: 0.091 (11217 hom.)
• Consequence: IGF2R NM_000876.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154
• Publications: 31 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]

CHP1P2 (HGNC:54896): (CHP1 pseudogene 2) This locus on chromosome 6q25.3 represents a single-exon transcribed pseudogene of the multi-exon calcium binding protein P22 gene which resides on chromosome 15q13.3. This pseudogene is situated within an intron region of the insulin-like growth factor 2 receptor gene (IGF2R). [provided by RefSeq, Jan 2009]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 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.6666C>T	p.Leu2222Leu	synonymous	Exon 45 of 48	NP_000867.3
	CHP1P2	NR_003288.2		n.*237C>T		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	ENST00000356956.6	TSL:1 MANE Select	c.6666C>T	p.Leu2222Leu	synonymous	Exon 45 of 48	ENSP00000349437.1
	IGF2R	ENST00000475584.1	TSL:3	n.3C>T		non_coding_transcript_exon	Exon 1 of 5
	IGF2R	ENST00000569097.2	TSL:6	n.3368C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21551 AN: 152036 Hom.: 2304 Cov.: 33

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0765

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.150 AC: 37338 AN: 248114 AF XY: 0.141

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.416

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.0643

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0908 AC: 132317 AN: 1457146 Hom.: 11217 Cov.: 31 AF XY: 0.0921 AC XY: 66721 AN XY: 724536

African (AFR) AF: 0.243 AC: 8087 AN: 33348

American (AMR) AF: 0.296 AC: 13092 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 288 AN: 26062

East Asian (EAS) AF: 0.424 AC: 16714 AN: 39436

South Asian (SAS) AF: 0.186 AC: 15915 AN: 85420

European-Finnish (FIN) AF: 0.0840 AC: 4481 AN: 53374

Middle Eastern (MID) AF: 0.0560 AC: 322 AN: 5750

European-Non Finnish (NFE) AF: 0.0608 AC: 67462 AN: 1109304

Other (OTH) AF: 0.0989 AC: 5956 AN: 60244

GnomAD4 genome AF: 0.142 AC: 21603 AN: 152154 Hom.: 2320 Cov.: 33 AF XY: 0.145 AC XY: 10806 AN XY: 74382

African (AFR) AF: 0.239 AC: 9926 AN: 41468

American (AMR) AF: 0.197 AC: 3015 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.412 AC: 2127 AN: 5168

South Asian (SAS) AF: 0.188 AC: 905 AN: 4820

European-Finnish (FIN) AF: 0.0765 AC: 811 AN: 10596

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0655 AC: 4454 AN: 68024

Other (OTH) AF: 0.133 AC: 280 AN: 2112

Alfa AF: 0.0937 Hom.: 4741

Bravo AF: 0.156

Asia WGS AF: 0.305 AC: 1061 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.5
DANN	Benign	0.87
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1803989; hg19: chr6-160517481; COSMIC: COSV63482114; COSMIC: COSV63482114;