rs11552587

chr6-160073896-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000876.4(IGF2R):c.5087A>G(p.Gln1696Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000992 in 1,614,212 control chromosomes in the GnomAD database, including 11 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (8 hom.)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.14

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 (MetaRNN=0.010492653).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00399 (608/152344) while in subpopulation AFR AF= 0.0126 (525/41584). AF 95% confidence interval is 0.0117. There are 3 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 609 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2R	NM_000876.4	c.5087A>G	p.Gln1696Arg	missense_variant	35/48	ENST00000356956.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2R	ENST00000356956.6	c.5087A>G	p.Gln1696Arg	missense_variant	35/48	1	NM_000876.4	P1

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152226 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00130 AC: 328 AN: 251432 Hom.: 1 AF XY: 0.00109 AC XY: 148 AN XY: 135902

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000680 AC: 994 AN: 1461868 Hom.: 8 Cov.: 32 AF XY: 0.000597 AC XY: 434 AN XY: 727236

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00399 AC: 608 AN: 152344 Hom.: 3 Cov.: 33 AF XY: 0.00366 AC XY: 273 AN XY: 74496

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.00484

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00155 AC: 188

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.059	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.16	N;.
REVEL	Benign	0.18
Sift	Benign	0.47	T;.
Sift4G	Benign	0.20	T;.
Polyphen		0.98	D;D
Vest4		0.28
MVP		0.54
MPC		0.66
ClinPred		0.041	T
GERP RS		5.6
Varity_R		0.31
gMVP		0.70

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: rs11552587; hg19: chr6-160494928;