6-160047277-G-A

Variant names:

• chr6-160047277-G-A
• rs6413491
• NM_000876.4:c.2170G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 12 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 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1424 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000876.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	NM_000876.4	MANE Select	c.2170G>A	p.Ala724Thr	missense	Exon 16 of 48	NP_000867.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2R	ENST00000356956.6	TSL:1 MANE Select	c.2170G>A	p.Ala724Thr	missense	Exon 16 of 48	ENSP00000349437.1
	IGF2R	ENST00000676781.1		n.*278G>A		non_coding_transcript_exon	Exon 17 of 49	ENSP00000504419.1
	IGF2R	ENST00000677704.1		n.2170G>A		non_coding_transcript_exon	Exon 16 of 49	ENSP00000503314.1

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

GnomAD2 exomes AF: 0.00262 AC: 653 AN: 249584 AF XY: 0.00199

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 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

African (AFR) AF: 0.0349 AC: 1165 AN: 33406

American (AMR) AF: 0.00217 AC: 97 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52488

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5762

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1111688

Other (OTH) AF: 0.00240 AC: 145 AN: 60344

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

African (AFR) AF: 0.0318 AC: 1321 AN: 41524

American (AMR) AF: 0.00425 AC: 65 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67966

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00331 Hom.: 20

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 v4.9

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
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
MetaSVM	Benign	-0.91	T
PhyloP100		0.68
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
Vest4		0.12
MVP		0.15
MPC		0.097
ClinPred		0.0014	T
GERP RS		1.5
Varity_R		0.058
gMVP		0.34
Mutation Taster		=91/9	polymorphism

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