6-160027232-A-G

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.694A>G(p.Thr232Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,222 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (13 hom.)
• Consequence: IGF2R NM_000876.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.48

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=0.013038099).
• BP6: Variant 6-160027232-A-G is Benign according to our data. Variant chr6-160027232-A-G is described in ClinVar as [Benign]. Clinvar id is 789187.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00653 (995/152348) while in subpopulation AFR AF= 0.0221 (917/41576). AF 95% confidence interval is 0.0209. There are 5 homozygotes in gnomad4. There are 480 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 994 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2R	NM_000876.4	c.694A>G	p.Thr232Ala	missense_variant	6/48	ENST00000356956.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2R	ENST00000356956.6	c.694A>G	p.Thr232Ala	missense_variant	6/48	1	NM_000876.4	P1
IGF2R	ENST00000677704.1	c.694A>G	p.Thr232Ala	missense_variant, NMD_transcript_variant	6/49
IGF2R	ENST00000676781.1	c.694A>G	p.Thr232Ala	missense_variant, NMD_transcript_variant	6/49

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 994 AN: 152230 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00172 AC: 433 AN: 251266 Hom.: 6 AF XY: 0.00135 AC XY: 183 AN XY: 135866

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000780 AC: 1140 AN: 1461874 Hom.: 13 Cov.: 31 AF XY: 0.000664 AC XY: 483 AN XY: 727238

Gnomad4 AFR exome AF: 0.0235

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00653 AC: 995 AN: 152348 Hom.: 5 Cov.: 33 AF XY: 0.00644 AC XY: 480 AN XY: 74494

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00731

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

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

Jul 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	13
Dann	Benign	0.93
DEOGEN2	Benign	0.088	T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.57	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.68	N;.
REVEL	Benign	0.10
Sift	Benign	0.40	T;.
Sift4G	Benign	0.13	T;.
Polyphen		0.0030	B;B
Vest4		0.10
MVP		0.25
MPC		0.093
ClinPred		0.0031	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.64

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: rs76235629; hg19: chr6-160448264;