6-160047351-T-C

Variant names:

• chr6-160047351-T-C
• rs998074
• NM_000876.4:c.2229+15T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000876.4(IGF2R):​c.2229+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 1,560,388 control chromosomes in the GnomAD database, including 192,908 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 0.53 (21849 hom., cov: 31)
  • Exomes 𝑓: 0.49 (171059 hom.)
• Consequence: IGF2R NM_000876.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.218
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.2229+15T>C		intron_variant	Intron 16 of 47	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.2229+15T>C		intron_variant	Intron 16 of 47	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000676781.1	n.*337+15T>C		intron_variant	Intron 17 of 48			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.2229+15T>C		intron_variant	Intron 16 of 48			ENSP00000503314.1

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80898 AN: 151852 Hom.: 21805 Cov.: 31

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.532

GnomAD2 exomes AF: 0.528 AC: 110564 AN: 209414 AF XY: 0.526

Gnomad AFR exome AF: 0.606

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.438

Gnomad EAS exome AF: 0.672

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.485

Gnomad OTH exome AF: 0.513

GnomAD4 exome AF: 0.490 AC: 690623 AN: 1408418 Hom.: 171059 Cov.: 31 AF XY: 0.492 AC XY: 342616 AN XY: 697002

African (AFR) AF: 0.607 AC: 19461 AN: 32042

American (AMR) AF: 0.535 AC: 21133 AN: 39528

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 10190 AN: 23004

East Asian (EAS) AF: 0.670 AC: 26323 AN: 39298

South Asian (SAS) AF: 0.534 AC: 42217 AN: 78998

European-Finnish (FIN) AF: 0.572 AC: 24634 AN: 43032

Middle Eastern (MID) AF: 0.549 AC: 2996 AN: 5462

European-Non Finnish (NFE) AF: 0.472 AC: 514135 AN: 1088748

Other (OTH) AF: 0.507 AC: 29534 AN: 58306

GnomAD4 genome AF: 0.533 AC: 80992 AN: 151970 Hom.: 21849 Cov.: 31 AF XY: 0.537 AC XY: 39875 AN XY: 74246

African (AFR) AF: 0.603 AC: 24973 AN: 41436

American (AMR) AF: 0.511 AC: 7810 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1542 AN: 3472

East Asian (EAS) AF: 0.671 AC: 3457 AN: 5152

South Asian (SAS) AF: 0.528 AC: 2546 AN: 4820

European-Finnish (FIN) AF: 0.590 AC: 6222 AN: 10552

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32745 AN: 67946

Other (OTH) AF: 0.537 AC: 1135 AN: 2114

Alfa AF: 0.483 Hom.: 15268

Bravo AF: 0.532

Asia WGS AF: 0.627 AC: 2181 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.7
DANN	Benign	0.21
PhyloP100		-0.22
Mutation Taster		=100/0	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: rs998074; hg19: chr6-160468383; COSMIC: COSV63627589;