rs8191808

Variant names:

• chr6-160048478-C-G
• rs8191808
• NM_000876.4:c.2449C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000876.4(IGF2R):​c.2449C>G​(p.Leu817Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,614,220 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (115 hom.)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.42
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005435288).
• BP6: Variant 6-160048478-C-G is Benign according to our data. Variant chr6-160048478-C-G is described in ClinVar as Benign. ClinVar VariationId is 771868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0059 (899/152382) while in subpopulation SAS AF = 0.0215 (104/4834). AF 95% confidence interval is 0.0182. There are 8 homozygotes in GnomAd4. There are 439 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 899 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	NM_000876.4	MANE Select	c.2449C>G	p.Leu817Val	missense	Exon 18 of 48	NP_000867.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	ENST00000356956.6	TSL:1 MANE Select	c.2449C>G	p.Leu817Val	missense	Exon 18 of 48	ENSP00000349437.1
	IGF2R	ENST00000676781.1		n.*557C>G		non_coding_transcript_exon	Exon 19 of 49	ENSP00000504419.1
	IGF2R	ENST00000677704.1		n.2449C>G		non_coding_transcript_exon	Exon 18 of 49	ENSP00000503314.1

Frequencies

GnomAD3 genomes AF: 0.00592 AC: 901 AN: 152264 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00611

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00692

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00955 AC: 2401 AN: 251456 AF XY: 0.0109

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00582

Gnomad NFE exome AF: 0.00805

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.00722 AC: 10548 AN: 1461838 Hom.: 115 Cov.: 32 AF XY: 0.00799 AC XY: 5814 AN XY: 727224

African (AFR) AF: 0.000866 AC: 29 AN: 33476

American (AMR) AF: 0.00586 AC: 262 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0307 AC: 803 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0237 AC: 2042 AN: 86254

European-Finnish (FIN) AF: 0.00584 AC: 312 AN: 53420

Middle Eastern (MID) AF: 0.0397 AC: 229 AN: 5768

European-Non Finnish (NFE) AF: 0.00564 AC: 6275 AN: 1111974

Other (OTH) AF: 0.00984 AC: 594 AN: 60394

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152382 Hom.: 8 Cov.: 33 AF XY: 0.00589 AC XY: 439 AN XY: 74524

African (AFR) AF: 0.00101 AC: 42 AN: 41586

American (AMR) AF: 0.00503 AC: 77 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0215 AC: 104 AN: 4834

European-Finnish (FIN) AF: 0.00611 AC: 65 AN: 10630

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00692 AC: 471 AN: 68042

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00863 Hom.: 9

Bravo AF: 0.00559

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00849 AC: 73

ExAC AF: 0.00938 AC: 1139

Asia WGS AF: 0.00866 AC: 31 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.0111

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IGF2R: BP4, BS1, BS2

Jul 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.088	T
Sift4G	Uncertain	0.012	D
Polyphen		0.98	D
Vest4		0.53
MVP		0.39
MPC		0.45
ClinPred		0.023	T
GERP RS		4.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.13
gMVP		0.62
Mutation Taster		=76/24	polymorphism

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: rs8191808; hg19: chr6-160469510; COSMIC: COSV63628518;