chr11-2143943-T-G

Variant names:

• chr11-2143943-T-G
• rs11603378
• ENST00000643349.2:c.*46+3623A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000643349.2(ENSG00000284779):​c.*46+3623A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,106 control chromosomes in the GnomAD database, including 4,564 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4564 hom., cov: 35)
• Consequence: ENSG00000284779 ENST00000643349.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290
• Publications: 11 publications found

Genes affected

ENSG00000284779 (HGNC:):

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]

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]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000643349.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF2	NM_001007139.6		c.-7+3623A>C		intron	N/A	NP_001007140.2
	INS-IGF2	NR_003512.4		n.708+3623A>C		intron	N/A
	IGF2-AS	NR_028043.2		n.437-2302T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000284779	ENST00000643349.2		c.*46+3623A>C		intron	N/A	ENSP00000495715.1
	IGF2	ENST00000481781.3	TSL:5	c.-7+3623A>C		intron	N/A	ENSP00000511998.1
	IGF2	ENST00000695541.1		c.-7+3623A>C		intron	N/A	ENSP00000511997.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36537 AN: 151994 Hom.: 4551 Cov.: 35

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.216

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.241 AC: 36595 AN: 152106 Hom.: 4564 Cov.: 35 AF XY: 0.233 AC XY: 17357 AN XY: 74370

African (AFR) AF: 0.274 AC: 11378 AN: 41516

American (AMR) AF: 0.191 AC: 2923 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 737 AN: 3468

East Asian (EAS) AF: 0.100 AC: 516 AN: 5162

South Asian (SAS) AF: 0.148 AC: 715 AN: 4826

European-Finnish (FIN) AF: 0.220 AC: 2337 AN: 10604

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17077 AN: 67912

Other (OTH) AF: 0.217 AC: 459 AN: 2114

Alfa AF: 0.235 Hom.: 5535

Bravo AF: 0.240

Asia WGS AF: 0.173 AC: 605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.3
DANN	Benign	0.22
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11603378; hg19: chr11-2165173;