6-160024661-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_000876.4(IGF2R):c.603C>T(p.Ser201=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,614,012 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0063 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (61 hom.)
• Consequence: IGF2R NM_000876.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.43

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 6-160024661-C-T is Benign according to our data. Variant chr6-160024661-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2657098.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-160024661-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00632 (962/152202) while in subpopulation NFE AF= 0.00635 (432/68010). AF 95% confidence interval is 0.00586. There are 11 homozygotes in gnomad4. There are 586 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 961 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2R	NM_000876.4	c.603C>T	p.Ser201=	synonymous_variant	5/48	ENST00000356956.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2R	ENST00000356956.6	c.603C>T	p.Ser201=	synonymous_variant	5/48	1	NM_000876.4	P1
IGF2R	ENST00000677704.1	c.603C>T	p.Ser201=	synonymous_variant, NMD_transcript_variant	5/49
IGF2R	ENST00000676781.1	c.603C>T	p.Ser201=	synonymous_variant, NMD_transcript_variant	5/49

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 961 AN: 152084 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00635

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00700 AC: 1760 AN: 251480 Hom.: 25 AF XY: 0.00678 AC XY: 922 AN XY: 135918

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.0370

Gnomad NFE exome AF: 0.00729

Gnomad OTH exome AF: 0.00586

GnomAD4 exome AF: 0.00688 AC: 10053 AN: 1461810 Hom.: 61 Cov.: 31 AF XY: 0.00654 AC XY: 4753 AN XY: 727218

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.0360

Gnomad4 NFE exome AF: 0.00682

Gnomad4 OTH exome AF: 0.00571

GnomAD4 genome AF: 0.00632 AC: 962 AN: 152202 Hom.: 11 Cov.: 32 AF XY: 0.00788 AC XY: 586 AN XY: 74410

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0386

Gnomad4 NFE AF: 0.00635

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00594 Hom.: 5

Bravo AF: 0.00352

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00569

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

IGF2R: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	4.6
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11759563; hg19: chr6-160445693;