chr6-160077017-G-A

Variant names:

• chr6-160077017-G-A
• rs3777404
• NM_000876.4:c.5316+1021G>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.5316+1021G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,084 control chromosomes in the GnomAD database, including 1,727 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 (1727 hom., cov: 33)
• Consequence: IGF2R NM_000876.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.778
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.5316+1021G>A		intron_variant	Intron 36 of 47	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.5316+1021G>A		intron_variant	Intron 36 of 47	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000650503.1	n.1926+1021G>A		intron_variant	Intron 13 of 23
IGF2R	ENST00000676781.1	n.*3424+1021G>A		intron_variant	Intron 37 of 48			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.*1187+1021G>A		intron_variant	Intron 37 of 48			ENSP00000503314.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 21994 AN: 151966 Hom.: 1727 Cov.: 33

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.165

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

GnomAD4 genome AF: 0.145 AC: 22019 AN: 152084 Hom.: 1727 Cov.: 33 AF XY: 0.144 AC XY: 10690 AN XY: 74338

African (AFR) AF: 0.155 AC: 6423 AN: 41470

American (AMR) AF: 0.129 AC: 1969 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 737 AN: 3472

East Asian (EAS) AF: 0.240 AC: 1239 AN: 5170

South Asian (SAS) AF: 0.178 AC: 856 AN: 4818

European-Finnish (FIN) AF: 0.119 AC: 1256 AN: 10586

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8914 AN: 67980

Other (OTH) AF: 0.168 AC: 354 AN: 2102

Alfa AF: 0.137 Hom.: 184

Bravo AF: 0.146

Asia WGS AF: 0.216 AC: 749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.50
DANN	Benign	0.61
PhyloP100		0.78
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: rs3777404; hg19: chr6-160498049; COSMIC: COSV63627637; COSMIC: COSV63627637;