rs8191754

chr6-160027292-C-Gchr6-160027292-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000876.4(IGF2R):c.754C>G(p.Leu252Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,260 control chromosomes in the GnomAD database, including 15,701 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1350 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14351 hom.)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017426014).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2R	NM_000876.4	c.754C>G	p.Leu252Val	missense_variant	6/48	ENST00000356956.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2R	ENST00000356956.6	c.754C>G	p.Leu252Val	missense_variant	6/48	1	NM_000876.4	P1
IGF2R	ENST00000677704.1	c.754C>G	p.Leu252Val	missense_variant, NMD_transcript_variant	6/49
IGF2R	ENST00000676781.1	c.754C>G	p.Leu252Val	missense_variant, NMD_transcript_variant	6/49

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20154 AN: 152168 Hom.: 1352 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0920

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.133 AC: 33205 AN: 249804 Hom.: 2396 AF XY: 0.137 AC XY: 18491 AN XY: 135092

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0686

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.223

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.138 AC: 201301 AN: 1460974 Hom.: 14351 Cov.: 32 AF XY: 0.139 AC XY: 101218 AN XY: 726736

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.0729

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.231

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.132 AC: 20147 AN: 152286 Hom.: 1350 Cov.: 33 AF XY: 0.130 AC XY: 9700 AN XY: 74470

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0917

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.0960

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.128

Alfa AF: 0.137 Hom.: 1109

Bravo AF: 0.130

TwinsUK AF: 0.141 AC: 523

ALSPAC AF: 0.140 AC: 540

ESP6500AA AF: 0.139 AC: 614

ESP6500EA AF: 0.131 AC: 1126

ExAC AF: 0.135 AC: 16397

Asia WGS AF: 0.202 AC: 703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.00012	P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.18
Sift	Uncertain	0.019	D;.
Sift4G	Uncertain	0.0090	D;.
Polyphen		0.87	P;P
Vest4		0.17
MPC		0.48
ClinPred		0.030	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.70
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8191754; hg19: chr6-160448324; COSMIC: COSV63626735; COSMIC: COSV63626735;