11-2133027-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000612.6(IGF2):c.503A>C(p.His168Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H168H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGF2 NM_000612.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.737

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3350923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF2	NM_000612.6	c.503A>C	p.His168Pro	missense_variant	4/4	ENST00000416167.7
INS-IGF2	NR_003512.4	n.1217A>C		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF2	ENST00000416167.7	c.503A>C	p.His168Pro	missense_variant	4/4	1	NM_000612.6	P4
	ENST00000643349.2	c.*555A>C		3_prime_UTR_variant	5/5			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jun 30, 2021

The c.671A>C (p.H224P) alteration is located in exon 5 (coding exon 4) of the IGF2 gene. This alteration results from a A to C substitution at nucleotide position 671, causing the histidine (H) at amino acid position 224 to be replaced by a proline (P). 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	0.067
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.39	T;.;T;T;.;.;T;T
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.53	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.071	D
MutationAssessor	Uncertain	2.6	M;.;M;M;.;.;M;M
MutationTaster	Benign	0.63	D;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N;N;N;.;D;N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.010	D;D;D;.;D;D;D;D
Sift4G	Benign	0.11	T;T;T;.;D;T;T;T
Polyphen		0.93	P;.;P;P;.;.;P;P
Vest4		0.31
MutPred		0.11		Gain of glycosylation at H168 (P = 0.0469);.;Gain of glycosylation at H168 (P = 0.0469);Gain of glycosylation at H168 (P = 0.0469);.;.;Gain of glycosylation at H168 (P = 0.0469);Gain of glycosylation at H168 (P = 0.0469);
MVP		0.95
MPC		1.9
ClinPred		0.72	D
GERP RS		1.9
Varity_R		0.44
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2154257;