11-2133025-C-G

Position:

• chr11-2133025-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000612.6(IGF2):​c.505G>C​(p.Gly169Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G169W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF2 NM_000612.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.579

Genes affected

IGF2 (HGNC:5466): (insulin like growth factor 2) This gene encodes a member of the insulin family of polypeptide growth factors, which are involved in development and growth. It is an imprinted gene, expressed only from the paternal allele, and epigenetic changes at this locus are associated with Wilms tumour, Beckwith-Wiedemann syndrome, rhabdomyosarcoma, and Silver-Russell syndrome. A read-through INS-IGF2 gene exists, whose 5' region overlaps the INS gene and the 3' region overlaps this gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24639052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2	NM_000612.6	c.505G>C	p.Gly169Arg	missense_variant	4/4	ENST00000416167.7
INS-IGF2	NR_003512.4	n.1219G>C		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2	ENST00000416167.7	c.505G>C	p.Gly169Arg	missense_variant	4/4	1	NM_000612.6	P4
	ENST00000643349.2	c.*557G>C		3_prime_UTR_variant	5/5			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2021

The c.673G>C (p.G225R) alteration is located in exon 5 (coding exon 4) of the IGF2 gene. This alteration results from a G to C substitution at nucleotide position 673, causing the glycine (G) at amino acid position 225 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.00094	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;T;T;.;.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.79	.;.;.;.;T;T;.;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.1	M;.;M;M;.;.;M;M
MutationTaster	Benign	0.96	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;N;N;.;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.067	T;T;T;.;D;T;T;T
Sift4G	Benign	0.10	T;T;T;.;D;T;T;T
Polyphen		0.89	P;.;P;P;.;.;P;P
Vest4		0.24
MutPred		0.11		Loss of catalytic residue at D165 (P = 0.1224);.;Loss of catalytic residue at D165 (P = 0.1224);Loss of catalytic residue at D165 (P = 0.1224);.;.;Loss of catalytic residue at D165 (P = 0.1224);Loss of catalytic residue at D165 (P = 0.1224);
MVP		0.92
MPC		1.8
ClinPred		0.76	D
GERP RS		2.1
Varity_R		0.078
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2154255;