NM_000876.4:c.289+8657A>G

Variant names:

• chr6-159999980-A-G
• rs3822844
• NM_000876.4:c.289+8657A>G

Variant summary

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

The NM_000876.4(IGF2R):​c.289+8657A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,018 control chromosomes in the GnomAD database, including 11,012 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 0.37 (11012 hom., cov: 32)
• Consequence: IGF2R NM_000876.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.837
• Publications: 5 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.289+8657A>G		intron_variant	Intron 2 of 47	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.289+8657A>G		intron_variant	Intron 2 of 47	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000676781.1	n.289+8657A>G		intron_variant	Intron 2 of 48			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.289+8657A>G		intron_variant	Intron 2 of 48			ENSP00000503314.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55424 AN: 151900 Hom.: 10969 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.696

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.338

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.365 AC: 55521 AN: 152018 Hom.: 11012 Cov.: 32 AF XY: 0.376 AC XY: 27941 AN XY: 74288

African (AFR) AF: 0.456 AC: 18893 AN: 41448

American (AMR) AF: 0.358 AC: 5481 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 972 AN: 3468

East Asian (EAS) AF: 0.697 AC: 3597 AN: 5158

South Asian (SAS) AF: 0.423 AC: 2040 AN: 4824

European-Finnish (FIN) AF: 0.420 AC: 4425 AN: 10538

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19048 AN: 67970

Other (OTH) AF: 0.346 AC: 731 AN: 2112

Alfa AF: 0.262 Hom.: 850

Bravo AF: 0.364

Asia WGS AF: 0.561 AC: 1954 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.4
DANN	Benign	0.72
PhyloP100		-0.84
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: rs3822844; hg19: chr6-160421012;