6-160009045-C-G

Variant names:

• chr6-160009045-C-G
• NM_000876.4:c.325C>G

Variant summary

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

The NM_000876.4(IGF2R):​c.325C>G​(p.Leu109Val) 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: -0.0770

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 rank	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.325C>G	p.Leu109Val	missense_variant	Exon 3 of 48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.325C>G	p.Leu109Val	missense_variant	Exon 3 of 48	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000676781.1	n.325C>G		non_coding_transcript_exon_variant	Exon 3 of 49			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.325C>G		non_coding_transcript_exon_variant	Exon 3 of 49			ENSP00000503314.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.325C>G (p.L109V) alteration is located in exon 3 (coding exon 3) of the IGF2R gene. This alteration results from a C to G substitution at nucleotide position 325, causing the leucine (L) at amino acid position 109 to be replaced by a valine (V). 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	Benign	0.12
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.24
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		1.0	D;D
Vest4		0.29
MutPred		0.76		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.61
MPC		0.093
ClinPred		0.94	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.51

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: chr6-160430077;