rs8191746

Positions:

• chr6-160024666-C-A
• chr6-160024666-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000876.4(IGF2R):​c.608C>A​(p.Pro203Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P203L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12661901).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.608C>A	p.Pro203Gln	missense_variant	5/48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.608C>A	p.Pro203Gln	missense_variant	5/48	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000676781.1	n.608C>A		non_coding_transcript_exon_variant	5/49			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.608C>A		non_coding_transcript_exon_variant	5/49			ENSP00000503314.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.054
Sift	Benign	0.13	T;.
Sift4G	Benign	0.22	T;.
Polyphen		0.84	P;P
Vest4		0.33
MutPred		0.34		Gain of solvent accessibility (P = 0.0365);Gain of solvent accessibility (P = 0.0365);
MVP		0.38
MPC		0.17
ClinPred		0.70	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.42

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: rs8191746; hg19: chr6-160445698;