rs8191904

chr6-160079596-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000876.4(IGF2R):c.5495G>A(p.Arg1832His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,452,580 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0092 (25 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (14 hom.)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0340

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029729903).
• BP6: Variant 6-160079596-G-A is Benign according to our data. Variant chr6-160079596-G-A is described in ClinVar as [Benign]. Clinvar id is 709060.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00923 (1406/152318) while in subpopulation AFR AF= 0.0319 (1325/41552). AF 95% confidence interval is 0.0305. There are 25 homozygotes in gnomad4. There are 639 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1391 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2R	NM_000876.4	c.5495G>A	p.Arg1832His	missense_variant	38/48	ENST00000356956.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2R	ENST00000356956.6	c.5495G>A	p.Arg1832His	missense_variant	38/48	1	NM_000876.4	P1
IGF2R	ENST00000650503.1	n.2105G>A		non_coding_transcript_exon_variant	15/24
IGF2R	ENST00000676781.1	c.*3603G>A		3_prime_UTR_variant, NMD_transcript_variant	39/49
IGF2R	ENST00000677704.1	c.*1366G>A		3_prime_UTR_variant, NMD_transcript_variant	39/49

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1391 AN: 152200 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00255 AC: 396 AN: 155224 Hom.: 6 AF XY: 0.00186 AC XY: 157 AN XY: 84260

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.000229

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000712

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000755

Gnomad OTH exome AF: 0.000319

GnomAD4 exome AF: 0.000861 AC: 1120 AN: 1300262 Hom.: 14 Cov.: 31 AF XY: 0.000787 AC XY: 501 AN XY: 636640

Gnomad4 AFR exome AF: 0.0326

Gnomad4 AMR exome AF: 0.00185

Gnomad4 ASJ exome AF: 0.000305

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000331

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000641

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00923 AC: 1406 AN: 152318 Hom.: 25 Cov.: 33 AF XY: 0.00858 AC XY: 639 AN XY: 74478

Gnomad4 AFR AF: 0.0319

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00742 Hom.: 755

Bravo AF: 0.0104

ESP6500AA AF: 0.0288 AC: 127

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00289 AC: 351

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	13
Dann	Benign	0.87
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.060	N
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.13	N;.
REVEL	Benign	0.036
Sift	Benign	0.62	T;.
Sift4G	Benign	0.46	T;.
Polyphen		0.0020	B;B
Vest4		0.071
MVP		0.27
MPC		0.50
ClinPred		0.0064	T
GERP RS		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.40

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: rs8191904; hg19: chr6-160500628; COSMIC: COSV63628294;