6-160024689-G-C

Position:

• chr6-160024689-G-C

Variant summary

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

The NM_000876.4(IGF2R):​c.631G>C​(p.Val211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.631G>C	p.Val211Leu	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.631G>C	p.Val211Leu	missense_variant	5/48	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000676781.1	n.631G>C		non_coding_transcript_exon_variant	5/49			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.631G>C		non_coding_transcript_exon_variant	5/49			ENSP00000503314.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2024

The c.631G>C (p.V211L) alteration is located in exon 5 (coding exon 5) of the IGF2R gene. This alteration results from a G to C substitution at nucleotide position 631, causing the valine (V) at amino acid position 211 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	0.071
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.20
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.025	D;.
Polyphen		0.98	D;D
Vest4		0.60
MutPred		0.63		Gain of catalytic residue at V211 (P = 0.0102);Gain of catalytic residue at V211 (P = 0.0102);
MVP		0.46
MPC		0.41
ClinPred		0.98	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-160445721;