6-160050720-C-T

Variant names:

• chr6-160050720-C-T
• rs8191821
• NM_000876.4:c.2694+68C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000876.4(IGF2R):​c.2694+68C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0579 in 1,396,136 control chromosomes in the GnomAD database, including 4,803 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 0.058 (601 hom., cov: 32)
  • Exomes 𝑓: 0.058 (4202 hom.)
• Consequence: IGF2R NM_000876.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• Publications: 7 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 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.2694+68C>T		intron	N/A	NP_000867.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	ENST00000356956.6	TSL:1 MANE Select	c.2694+68C>T		intron	N/A	ENSP00000349437.1
	IGF2R	ENST00000676781.1		n.*802+68C>T		intron	N/A	ENSP00000504419.1
	IGF2R	ENST00000677704.1		n.2694+68C>T		intron	N/A	ENSP00000503314.1

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 8749 AN: 152126 Hom.: 596 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0512

GnomAD4 exome AF: 0.0580 AC: 72117 AN: 1243892 Hom.: 4202 AF XY: 0.0586 AC XY: 35749 AN XY: 610466

African (AFR) AF: 0.0101 AC: 290 AN: 28680

American (AMR) AF: 0.224 AC: 6715 AN: 30040

Ashkenazi Jewish (ASJ) AF: 0.00781 AC: 161 AN: 20616

East Asian (EAS) AF: 0.314 AC: 11096 AN: 35304

South Asian (SAS) AF: 0.105 AC: 7167 AN: 68206

European-Finnish (FIN) AF: 0.0572 AC: 2623 AN: 45888

Middle Eastern (MID) AF: 0.0198 AC: 79 AN: 3988

European-Non Finnish (NFE) AF: 0.0427 AC: 40963 AN: 958798

Other (OTH) AF: 0.0577 AC: 3023 AN: 52372

GnomAD4 genome AF: 0.0575 AC: 8757 AN: 152244 Hom.: 601 Cov.: 32 AF XY: 0.0605 AC XY: 4508 AN XY: 74454

African (AFR) AF: 0.0127 AC: 528 AN: 41548

American (AMR) AF: 0.142 AC: 2171 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.324 AC: 1672 AN: 5166

South Asian (SAS) AF: 0.104 AC: 504 AN: 4826

European-Finnish (FIN) AF: 0.0499 AC: 529 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0466 AC: 3170 AN: 68020

Other (OTH) AF: 0.0563 AC: 119 AN: 2112

Alfa AF: 0.0516 Hom.: 621

Bravo AF: 0.0659

Asia WGS AF: 0.216 AC: 752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.9
DANN	Benign	0.61
PhyloP100		0.12
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: rs8191821; hg19: chr6-160471752; COSMIC: COSV63631854;