rs121434587

Positions:

• chr6-160069961-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000876.4(IGF2R):​c.4346G>T​(p.Gly1449Val) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.25

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 6-160069961-G-T is Pathogenic according to our data. Variant chr6-160069961-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14795.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.4346G>T	p.Gly1449Val	missense_variant	31/48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.4346G>T	p.Gly1449Val	missense_variant	31/48	1	NM_000876.4	ENSP00000349437	P1
IGF2R	ENST00000650503.1	n.956G>T		non_coding_transcript_exon_variant	8/24
IGF2R	ENST00000676781.1	c.*2454G>T		3_prime_UTR_variant, NMD_transcript_variant	32/49			ENSP00000504419
IGF2R	ENST00000677704.1	c.*217G>T		3_prime_UTR_variant, NMD_transcript_variant	32/49			ENSP00000503314

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hepatocellular carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.58	.;T
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.2	D;.
REVEL	Benign	0.21
Sift	Benign	0.031	D;.
Sift4G	Benign	0.067	T;.
Polyphen		0.90	P;P
Vest4		0.37
MutPred		0.75		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.67
MPC		1.1
ClinPred		0.71	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121434587; hg19: chr6-160490993;