rs8191754

Variant names:

• chr6-160027292-C-G
• rs8191754
• NM_000876.4:c.754C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-160027292-C-G
• chr6-160027292-C-T

Variant summary

Our verdict is Benign. The variant received -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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 42 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.754C>G	p.Leu252Val	missense_variant	Exon 6 of 48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.754C>G	p.Leu252Val	missense_variant	Exon 6 of 48	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000676781.1	n.754C>G		non_coding_transcript_exon_variant	Exon 6 of 49			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.754C>G		non_coding_transcript_exon_variant	Exon 6 of 49			ENSP00000503314.1

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

GnomAD2 exomes AF: 0.133 AC: 33205 AN: 249804 AF XY: 0.137

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 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

African (AFR) AF: 0.136 AC: 4556 AN: 33454

American (AMR) AF: 0.0729 AC: 3256 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2993 AN: 26126

East Asian (EAS) AF: 0.231 AC: 9145 AN: 39660

South Asian (SAS) AF: 0.178 AC: 15315 AN: 86170

European-Finnish (FIN) AF: 0.106 AC: 5638 AN: 53372

Middle Eastern (MID) AF: 0.136 AC: 768 AN: 5632

European-Non Finnish (NFE) AF: 0.136 AC: 151262 AN: 1111574

Other (OTH) AF: 0.139 AC: 8368 AN: 60330

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

African (AFR) AF: 0.137 AC: 5690 AN: 41548

American (AMR) AF: 0.0917 AC: 1404 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3470

East Asian (EAS) AF: 0.222 AC: 1150 AN: 5174

South Asian (SAS) AF: 0.191 AC: 924 AN: 4826

European-Finnish (FIN) AF: 0.0960 AC: 1019 AN: 10616

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9060 AN: 68022

Other (OTH) AF: 0.128 AC: 271 AN: 2116

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
LIST_S2	Benign	0.75	.;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.2	T
PhyloP100		3.0
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
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8191754; hg19: chr6-160448324; COSMIC: COSV63626735; COSMIC: COSV63626735;