rs8191844

Positions:

• chr6-160061897-C-G
• chr6-160061897-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000876.4(IGF2R):​c.3551C>G​(p.Thr1184Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00174 in 1,614,126 control chromosomes in the GnomAD database, including 47 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 0.0092 (26 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (21 hom.)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24

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=0.0097438395).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00923 (1405/152240) while in subpopulation AFR AF= 0.0316 (1314/41548). AF 95% confidence interval is 0.0302. There are 26 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1405 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2R	NM_000876.4	c.3551C>G	p.Thr1184Ser	missense_variant	25/48	ENST00000356956.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2R	ENST00000356956.6	c.3551C>G	p.Thr1184Ser	missense_variant	25/48	1	NM_000876.4	P1
IGF2R	ENST00000650503.1	n.161C>G		non_coding_transcript_exon_variant	2/24
IGF2R	ENST00000677704.1	c.3551C>G	p.Thr1184Ser	missense_variant, NMD_transcript_variant	25/49
IGF2R	ENST00000676781.1	c.*1659C>G		3_prime_UTR_variant, NMD_transcript_variant	26/49

Frequencies

GnomAD3 genomes AF: 0.00924 AC: 1405 AN: 152122 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00242 AC: 609 AN: 251458 Hom.: 6 AF XY: 0.00167 AC XY: 227 AN XY: 135904

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000958 AC: 1401 AN: 1461886 Hom.: 21 Cov.: 32 AF XY: 0.000781 AC XY: 568 AN XY: 727246

Gnomad4 AFR exome AF: 0.0346

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00923 AC: 1405 AN: 152240 Hom.: 26 Cov.: 33 AF XY: 0.00893 AC XY: 665 AN XY: 74454

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00997

Alfa AF: 0.000455 Hom.: 1

Bravo AF: 0.0108

ESP6500AA AF: 0.0288 AC: 127

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00280 AC: 340

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0097	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.19
Sift	Benign	0.064	T;.
Sift4G	Uncertain	0.034	D;.
Polyphen		1.0	D;D
Vest4		0.68
MutPred		0.53		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.49
MPC		1.2
ClinPred		0.025	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.68

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: rs8191844; hg19: chr6-160482929;