6-159969298-C-G

Variant names:

• chr6-159969298-C-G
• rs1201276099
• NM_000876.4:c.52C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000876.4(IGF2R):​c.52C>G​(p.Arg18Gly) 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. 13/21 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. R18L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.737
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23798507).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000876.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	NM_000876.4	MANE Select	c.52C>G	p.Arg18Gly	missense	Exon 1 of 48	NP_000867.3	P11717

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	ENST00000356956.6	TSL:1 MANE Select	c.52C>G	p.Arg18Gly	missense	Exon 1 of 48	ENSP00000349437.1	P11717
	IGF2R	ENST00000676781.1		n.52C>G		non_coding_transcript_exon	Exon 1 of 49	ENSP00000504419.1	A0A7I2YQS7
	IGF2R	ENST00000677704.1		n.52C>G		non_coding_transcript_exon	Exon 1 of 49	ENSP00000503314.1	A0A7I2V381

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.74
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.082
Sift	Benign	0.11	T
Sift4G	Uncertain	0.038	D
Polyphen		0.98	D
Vest4		0.14
MutPred		0.22		Gain of relative solvent accessibility (P = 0.0249)
MVP		0.30
MPC		0.12
ClinPred		0.22	T
GERP RS		2.1
PromoterAI		0.068	Neutral
Varity_R		0.15
gMVP		0.62
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1201276099; hg19: chr6-160390330;