rs6413491

Positions:

• chr6-160047277-G-A
• chr6-160047277-G-C
• chr6-160047277-G-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.2170G>A​(p.Ala724Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,612,466 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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 0.0094 (30 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.678

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=0.0044843554).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00936 (1424/152178) while in subpopulation AFR AF= 0.0318 (1321/41524). AF 95% confidence interval is 0.0304. There are 30 homozygotes in gnomad4. There are 694 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1424 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2R	NM_000876.4	c.2170G>A	p.Ala724Thr	missense_variant	16/48	ENST00000356956.6	NP_000867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2R	ENST00000356956.6	c.2170G>A	p.Ala724Thr	missense_variant	16/48	1	NM_000876.4	ENSP00000349437.1
IGF2R	ENST00000676781.1	n.*278G>A		non_coding_transcript_exon_variant	17/49			ENSP00000504419.1
IGF2R	ENST00000677704.1	n.2170G>A		non_coding_transcript_exon_variant	16/49			ENSP00000503314.1
IGF2R	ENST00000676781.1	n.*278G>A		3_prime_UTR_variant	17/49			ENSP00000504419.1

Frequencies

GnomAD3 genomes AF: 0.00935 AC: 1422 AN: 152060 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00262 AC: 653 AN: 249584 Hom.: 9 AF XY: 0.00199 AC XY: 268 AN XY: 134906

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.00109 AC: 1588 AN: 1460288 Hom.: 22 Cov.: 34 AF XY: 0.000917 AC XY: 666 AN XY: 726500

Gnomad4 AFR exome AF: 0.0349

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00936 AC: 1424 AN: 152178 Hom.: 30 Cov.: 33 AF XY: 0.00933 AC XY: 694 AN XY: 74414

Gnomad4 AFR AF: 0.0318

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.000734 Hom.: 3

Bravo AF: 0.0108

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0313 AC: 138

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00312 AC: 379

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.96
DEOGEN2	Benign	0.098	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.85	.;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.45	N;.
REVEL	Benign	0.029
Sift	Benign	0.17	T;.
Sift4G	Benign	0.25	T;.
Polyphen		0.071	B;B
Vest4		0.12
MVP		0.15
MPC		0.097
ClinPred		0.0014	T
GERP RS		1.5
Varity_R		0.058
gMVP		0.34

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: rs6413491; hg19: chr6-160468309; COSMIC: COSV63627286;