chr11-2133063-C-T

Position:

• chr11-2133063-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000416167.7(IGF2):​c.467G>A​(p.Arg156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,604,884 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0097 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: IGF2 ENST00000416167.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.881

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]

ENSG00000284779 (HGNC:):

INS-IGF2 (HGNC:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0084246695).
• BP6: Variant 11-2133063-C-T is Benign according to our data. Variant chr11-2133063-C-T is described in ClinVar as [Benign]. Clinvar id is 713986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2133063-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00965 (1470/152300) while in subpopulation AFR AF= 0.033 (1373/41560). AF 95% confidence interval is 0.0316. There are 27 homozygotes in gnomad4. There are 643 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1470 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF2	NM_000612.6	c.467G>A	p.Arg156His	missense_variant	4/4	ENST00000416167.7	NP_000603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF2	ENST00000416167.7	c.467G>A	p.Arg156His	missense_variant	4/4	1	NM_000612.6	ENSP00000414497.2
IGF2	ENST00000381392.5	c.476G>A	p.Arg159His	missense_variant	4/4	1		ENSP00000370799.1
IGF2	ENST00000381406.8	c.476G>A	p.Arg159His	missense_variant	4/4	2		ENSP00000370813.4
ENSG00000284779	ENST00000643349.2	c.*519G>A		3_prime_UTR_variant	5/5			ENSP00000495715.1

Frequencies

GnomAD3 genomes AF: 0.00964 AC: 1467 AN: 152182 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00259 AC: 629 AN: 243068 Hom.: 12 AF XY: 0.00179 AC XY: 237 AN XY: 132062

Gnomad AFR exome AF: 0.0341

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.00122 AC: 1775 AN: 1452584 Hom.: 30 Cov.: 31 AF XY: 0.00113 AC XY: 819 AN XY: 721696

Gnomad4 AFR exome AF: 0.0360

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00965 AC: 1470 AN: 152300 Hom.: 27 Cov.: 33 AF XY: 0.00863 AC XY: 643 AN XY: 74474

Gnomad4 AFR AF: 0.0330

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00212 Hom.: 4

Bravo AF: 0.0109

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0318 AC: 140

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00324 AC: 393

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Uncertain	0.58	D;.;D;D;.;.;D;D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.88	.;.;.;.;D;D;.;D
MetaRNN	Benign	0.0084	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M;.;M;M;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.4	N;N;N;.;D;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.014	D;D;D;.;T;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;.;D;D;D;D
Polyphen		0.047	B;.;B;B;.;.;B;B
Vest4		0.14
MVP		0.68
MPC		0.89
ClinPred		0.042	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.076
gMVP		0.62

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: rs61732764; hg19: chr11-2154293;