NM_000876.4:c.6051C>G

Variant names:

• chr6-160084167-C-G
• rs614754
• NM_000876.4:c.6051C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000876.4(IGF2R):​c.6051C>G​(p.Leu2017Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,613,310 control chromosomes in the GnomAD database, including 785,500 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.

• Frequency:
  • Genomes: 𝑓 0.99 (74684 hom., cov: 31)
  • Exomes 𝑓: 0.99 (710816 hom.)
• Consequence: IGF2R NM_000876.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.939
• Publications: 26 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=-0.939 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.6051C>G	p.Leu2017Leu	synonymous_variant	Exon 40 of 48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.6051C>G	p.Leu2017Leu	synonymous_variant	Exon 40 of 48	1	NM_000876.4	ENSP00000349437.1

Frequencies

GnomAD3 genomes AF: 0.990 AC: 150698 AN: 152166 Hom.: 74626 Cov.: 31

Gnomad AFR AF: 0.997

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.990

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.990

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.990

GnomAD2 exomes AF: 0.992 AC: 249051 AN: 251128 AF XY: 0.992

Gnomad AFR exome AF: 0.997

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.988

Gnomad NFE exome AF: 0.986

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.986 AC: 1441141 AN: 1461026 Hom.: 710816 Cov.: 37 AF XY: 0.987 AC XY: 717486 AN XY: 726880

African (AFR) AF: 0.997 AC: 33373 AN: 33458

American (AMR) AF: 0.995 AC: 44509 AN: 44718

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26131 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39694 AN: 39694

South Asian (SAS) AF: 1.00 AC: 86229 AN: 86244

European-Finnish (FIN) AF: 0.988 AC: 52780 AN: 53418

Middle Eastern (MID) AF: 0.999 AC: 5747 AN: 5754

European-Non Finnish (NFE) AF: 0.984 AC: 1093047 AN: 1111246

Other (OTH) AF: 0.988 AC: 59631 AN: 60360

GnomAD4 genome AF: 0.990 AC: 150815 AN: 152284 Hom.: 74684 Cov.: 31 AF XY: 0.991 AC XY: 73796 AN XY: 74446

African (AFR) AF: 0.997 AC: 41414 AN: 41554

American (AMR) AF: 0.990 AC: 15145 AN: 15298

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3471 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5165 AN: 5166

South Asian (SAS) AF: 1.00 AC: 4822 AN: 4824

European-Finnish (FIN) AF: 0.990 AC: 10509 AN: 10610

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.985 AC: 66997 AN: 68042

Other (OTH) AF: 0.991 AC: 2094 AN: 2114

Alfa AF: 0.988 Hom.: 24097

Bravo AF: 0.991

Asia WGS AF: 0.999 AC: 3475 AN: 3478

EpiCase AF: 0.988

EpiControl AF: 0.987

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.073
DANN	Benign	0.53
PhyloP100		-0.94
Mutation Taster		=99/1	polymorphism (auto)

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: rs614754; hg19: chr6-160505199; COSMIC: COSV108181796; COSMIC: COSV108181796;