rs3777404

Positions:

• chr6-160077017-G-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.5316+1021G>A		intron_variant		ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.5316+1021G>A		intron_variant		1	NM_000876.4	ENSP00000349437	P1
IGF2R	ENST00000676781.1	c.*3424+1021G>A		intron_variant, NMD_transcript_variant				ENSP00000504419
IGF2R	ENST00000677704.1	c.*1187+1021G>A		intron_variant, NMD_transcript_variant				ENSP00000503314
IGF2R	ENST00000650503.1	n.1926+1021G>A		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.168

Alfa AF: 0.136 Hom.: 177

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3777404; hg19: chr6-160498049; COSMIC: COSV63627637; COSMIC: COSV63627637;