11-2147625-C-T

Position:

• chr11-2147625-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000643349.2(ENSG00000284779):​c.437G>A​(p.Arg146His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,089,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ENST00000643349.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.15

Genes affected

(HGNC:):

IGF2-AS (HGNC:14062): (IGF2 antisense RNA) This gene is expressed in antisense to the insulin-like growth factor 2 (IGF2) gene and is imprinted and paternally expressed. It is thought to be non-coding because the putative protein is not conserved and translation is predicted to trigger nonsense mediated decay (NMD). Transcripts from this gene are produced in tumors and may function to suppress cell growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043969035).
• BP6: Variant 11-2147625-C-T is Benign according to our data. Variant chr11-2147625-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3109906.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS-IGF2	NR_003512.4	n.649G>A		non_coding_transcript_exon_variant	4/7
IGF2-AS	NR_028043.2	n.1027C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000643349.2	c.437G>A	p.Arg146His	missense_variant	2/5			ENSP00000495715	P1
IGF2-AS	ENST00000381361.4	n.1022C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000101 AC: 11 AN: 1089468 Hom.: 0 Cov.: 29 AF XY: 0.0000136 AC XY: 7 AN XY: 515054

Gnomad4 AFR exome AF: 0.0000422

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000145

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.0000228

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	4.0
DANN	Benign	0.63
DEOGEN2	Benign	0.010	.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	-0.20	.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	-0.48	.;N
REVEL	Benign	0.25
Sift	Benign	0.22	.;T
Sift4G	Benign	0.88	.;T
Polyphen		0.0	.;B
Vest4		0.025
MutPred		0.26		.;Loss of solvent accessibility (P = 6e-04);
MVP		0.15
MPC		0.32
ClinPred		0.19	T
GERP RS		-3.2
Varity_R		0.023
gMVP		0.070

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: rs1234730342; hg19: chr11-2168855; COSMIC: COSV56100602; COSMIC: COSV56100602;