rs9456497

chr6-160022396-A-Gchr6-160022396-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000876.4(IGF2R):c.514-2176A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 152,152 control chromosomes in the GnomAD database, including 3,168 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 0.18 (3168 hom., cov: 32)
• Consequence: IGF2R NM_000876.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.620

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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2R	NM_000876.4	c.514-2176A>G		intron_variant		ENST00000356956.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2R	ENST00000356956.6	c.514-2176A>G		intron_variant		1	NM_000876.4	P1
IGF2R	ENST00000676781.1	c.514-2176A>G		intron_variant, NMD_transcript_variant
IGF2R	ENST00000677704.1	c.514-2176A>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28027 AN: 152034 Hom.: 3163 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.184 AC: 28038 AN: 152152 Hom.: 3168 Cov.: 32 AF XY: 0.190 AC XY: 14097 AN XY: 74386

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.519

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.191

Alfa AF: 0.132 Hom.: 345

Bravo AF: 0.188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.99
Dann	Benign	0.37

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: rs9456497; hg19: chr6-160443428;