6-159969265-C-G

Variant names:

• chr6-159969265-C-G
• rs1018663090
• NM_000876.4:c.19C>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000876.4(IGF2R):​c.19C>G​(p.Arg7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000944 in 148,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0790

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12845963).
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.19C>G	p.Arg7Gly	missense_variant	Exon 1 of 48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.19C>G	p.Arg7Gly	missense_variant	Exon 1 of 48	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000676781.1	n.19C>G		non_coding_transcript_exon_variant	Exon 1 of 49			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.19C>G		non_coding_transcript_exon_variant	Exon 1 of 49			ENSP00000503314.1

Frequencies

GnomAD3 genomes AF: 0.0000944 AC: 14 AN: 148250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000416 AC: 4 AN: 961158 Hom.: 0 Cov.: 30 AF XY: 0.00000220 AC XY: 1 AN XY: 454006

Gnomad4 AFR exome AF: 0.0000537

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000118

Gnomad4 OTH exome AF: 0.0000574

GnomAD4 genome AF: 0.0000944 AC: 14 AN: 148358 Hom.: 0 Cov.: 32 AF XY: 0.0000691 AC XY: 5 AN XY: 72324

Gnomad4 AFR AF: 0.000316

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19C>G (p.R7G) alteration is located in exon 1 (coding exon 1) of the IGF2R gene. This alteration results from a C to G substitution at nucleotide position 19, causing the arginine (R) at amino acid position 7 to be replaced by a glycine (G). 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	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.54	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.054
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.040	D;.
Polyphen		0.59	P;P
Vest4		0.18
MutPred		0.38		Loss of methylation at R7 (P = 0.007);Loss of methylation at R7 (P = 0.007);
MVP		0.24
MPC		0.12
ClinPred		0.43	T
GERP RS		0.32
Varity_R		0.15
gMVP		0.59

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: rs1018663090; hg19: chr6-160390297;