6-160073377-A-G

Position:

• chr6-160073377-A-G

Variant summary

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

The NM_000876.4(IGF2R):​c.4855A>G​(p.Arg1619Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,614,202 control chromosomes in the GnomAD database, including 629,117 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.91 (63506 hom., cov: 35)
  • Exomes 𝑓: 0.88 (565611 hom.)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02

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=8.4388586E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.4855A>G	p.Arg1619Gly	missense_variant	34/48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.4855A>G	p.Arg1619Gly	missense_variant	34/48	1	NM_000876.4	ENSP00000349437.1

Frequencies

GnomAD3 genomes AF: 0.912 AC: 138820 AN: 152232 Hom.: 63442 Cov.: 35

Gnomad AFR AF: 0.975

Gnomad AMI AF: 0.910

Gnomad AMR AF: 0.913

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 0.830

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.916

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.878

Gnomad OTH AF: 0.909

GnomAD3 exomes AF: 0.899 AC: 225927 AN: 251418 Hom.: 101765 AF XY: 0.896 AC XY: 121751 AN XY: 135896

Gnomad AFR exome AF: 0.977

Gnomad AMR exome AF: 0.942

Gnomad ASJ exome AF: 0.949

Gnomad EAS exome AF: 0.839

Gnomad SAS exome AF: 0.900

Gnomad FIN exome AF: 0.908

Gnomad NFE exome AF: 0.877

Gnomad OTH exome AF: 0.900

GnomAD4 exome AF: 0.879 AC: 1285017 AN: 1461852 Hom.: 565611 Cov.: 62 AF XY: 0.880 AC XY: 640053 AN XY: 727218

Gnomad4 AFR exome AF: 0.981

Gnomad4 AMR exome AF: 0.939

Gnomad4 ASJ exome AF: 0.946

Gnomad4 EAS exome AF: 0.832

Gnomad4 SAS exome AF: 0.901

Gnomad4 FIN exome AF: 0.908

Gnomad4 NFE exome AF: 0.870

Gnomad4 OTH exome AF: 0.890

GnomAD4 genome AF: 0.912 AC: 138943 AN: 152350 Hom.: 63506 Cov.: 35 AF XY: 0.912 AC XY: 67937 AN XY: 74494

Gnomad4 AFR AF: 0.975

Gnomad4 AMR AF: 0.914

Gnomad4 ASJ AF: 0.951

Gnomad4 EAS AF: 0.831

Gnomad4 SAS AF: 0.889

Gnomad4 FIN AF: 0.916

Gnomad4 NFE AF: 0.878

Gnomad4 OTH AF: 0.909

Alfa AF: 0.889 Hom.: 134553

Bravo AF: 0.916

TwinsUK AF: 0.869 AC: 3223

ALSPAC AF: 0.871 AC: 3356

ESP6500AA AF: 0.969 AC: 4269

ESP6500EA AF: 0.881 AC: 7575

ExAC AF: 0.896 AC: 108806

Asia WGS AF: 0.878 AC: 3053 AN: 3478

EpiCase AF: 0.884

EpiControl AF: 0.882

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.29
DEOGEN2	Benign	0.052	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.12	.;T
MetaRNN	Benign	8.4e-7	T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	3.6	N;.
REVEL	Benign	0.087
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;B
Vest4		0.013
MPC		0.52
ClinPred		0.00093	T
GERP RS		4.4
Varity_R		0.056
gMVP		0.70

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: rs629849; hg19: chr6-160494409;