11-2143943-T-G

Variant summary

Our verdict is Benign. Variant got -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: ENST00000643349.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS-IGF2	NR_003512.4	n.708+3623A>C		intron_variant, non_coding_transcript_variant
IGF2-AS	NR_028043.2	n.437-2302T>G		intron_variant, non_coding_transcript_variant
IGF2	NM_001007139.6	c.-7+3623A>C		intron_variant
IGF2-AS	NR_133657.1	n.437-2413T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000643349.2	c.*46+3623A>C		intron_variant				P1
IGF2-AS	ENST00000381361.4	n.432-2302T>G		intron_variant, non_coding_transcript_variant		2

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

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.100

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.217

Alfa AF: 0.231 Hom.: 3976

Bravo AF: 0.240

Asia WGS AF: 0.173 AC: 605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	6.3
Dann	Benign	0.22

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11603378; hg19: chr11-2165173;