rs554804044

Variant names:

• chr11-2133025-C-A
• rs554804044
• NM_000612.6:c.505G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2133025-C-A
• chr11-2133025-C-G
• chr11-2133025-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000612.6(IGF2):​c.505G>T​(p.Gly169Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000475 in 1,557,890 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G169R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (1 hom.)
• Consequence: IGF2 NM_000612.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.579
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08248708).
• BP6: Variant 11-2133025-C-A is Benign according to our data. Variant chr11-2133025-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2409469.
• BS2: High AC in GnomAdExome4 at 73 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000612.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2	NM_000612.6	MANE Select	c.505G>T	p.Gly169Trp	missense	Exon 4 of 4	NP_000603.1	P01344-1
	IGF2	NM_001127598.3		c.673G>T	p.Gly225Trp	missense	Exon 5 of 5	NP_001121070.1	P01344-3
	IGF2	NM_001007139.6		c.505G>T	p.Gly169Trp	missense	Exon 5 of 5	NP_001007140.2	P01344-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2	ENST00000416167.7	TSL:1 MANE Select	c.505G>T	p.Gly169Trp	missense	Exon 4 of 4	ENSP00000414497.2	P01344-1
	IGF2	ENST00000434045.6	TSL:1	c.673G>T	p.Gly225Trp	missense	Exon 5 of 5	ENSP00000391826.2	P01344-3
	IGF2	ENST00000381392.5	TSL:1	c.514G>T	p.Gly172Trp	missense	Exon 4 of 4	ENSP00000370799.1	P01344-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000817 AC: 17 AN: 208104 AF XY: 0.000105

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000519 AC: 73 AN: 1405756 Hom.: 1 Cov.: 31 AF XY: 0.0000792 AC XY: 55 AN XY: 694206

African (AFR) AF: 0.00 AC: 0 AN: 31142

American (AMR) AF: 0.00 AC: 0 AN: 35120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23584

East Asian (EAS) AF: 0.00 AC: 0 AN: 37570

South Asian (SAS) AF: 0.000854 AC: 68 AN: 79632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51344

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5500

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084124

Other (OTH) AF: 0.0000520 AC: 3 AN: 57740

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000660 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.082	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.58
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.27
Sift	Benign	0.042	D
Sift4G	Uncertain	0.020	D
Polyphen		0.033	B
Vest4		0.21
MutPred		0.20		Loss of catalytic residue at G169 (P = 0.0596)
MVP		0.88
MPC		1.0
ClinPred		0.13	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.48
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs554804044; hg19: chr11-2154255;