19-56814215-AGCAGCCTCCACTTCTGGCTCG-AGCAGCCTCCACTTCTGGCTCGGCAGCCTCCACTTCTGGCTCGGCAGCCTCCACTTCTGGCTCG

Variant names:

• chr19-56814215-A-AGCAGCCTCCACTTCTGGCTCGGCAGCCTCCACTTCTGGCTCG
• NM_006210.3:c.4226_4227insCGAGCCAGAAGTGGAGGCTGCCGAGCCAGAAGTGGAGGCTGC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_006210.3(PEG3):​c.4226_4227insCGAGCCAGAAGTGGAGGCTGCCGAGCCAGAAGTGGAGGCTGC​(p.Ala1409_Glu1410insGluProGluValGluAlaAlaGluProGluValGluAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,822 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PEG3 NM_006210.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10

Genes affected

PEG3 (HGNC:8826): (paternally expressed 3) In human, ZIM2 and PEG3 are treated as two distinct genes though they share multiple 5' exons and a common promoter and both genes are paternally expressed (PMID:15203203). Alternative splicing events connect their shared 5' exons either with the remaining 4 exons unique to ZIM2, or with the remaining 2 exons unique to PEG3. In contrast, in other mammals ZIM2 does not undergo imprinting and, in mouse, cow, and likely other mammals as well, the ZIM2 and PEG3 genes do not share exons. Human PEG3 protein belongs to the Kruppel C2H2-type zinc finger protein family. PEG3 may play a role in cell proliferation and p53-mediated apoptosis. PEG3 has also shown tumor suppressor activity and tumorigenesis in glioma and ovarian cells. Alternative splicing of this PEG3 gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Sep 2009]

ZIM2 (HGNC:12875): (zinc finger imprinted 2) In human, ZIM2 and PEG3 (GeneID:5178) are two distinct genes that share a set of 5' exons and have a common promoter, and both genes are paternally expressed. Alternative splicing events connect the shared exons either with the remaining 4 exons unique to ZIM2, or with the remaining 2 exons unique to PEG3. This is in contrast to mouse and cow, where ZIM2 and PEG3 genes do not share exons in common, and the imprinting status of ZIM2 is also not conserved amongst mammals. Additional 5' alternatively spliced transcripts encoding the same protein have been found for the human ZIM2 gene. [provided by RefSeq, Oct 2010]

ENSG00000286125 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006210.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEG3	NM_006210.3	c.4226_4227insCGAGCCAGAAGTGGAGGCTGCCGAGCCAGAAGTGGAGGCTGC	p.Ala1409_Glu1410insGluProGluValGluAlaAlaGluProGluValGluAlaAla	disruptive_inframe_insertion	Exon 10 of 10	ENST00000326441.15	NP_006201.1
ZIM2	NM_001387356.1	c.490+3530_490+3531insCGAGCCAGAAGTGGAGGCTGCCGAGCCAGAAGTGGAGGCTGC		intron_variant	Intron 9 of 12	ENST00000629319.3	NP_001374285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEG3	ENST00000326441.15	c.4226_4227insCGAGCCAGAAGTGGAGGCTGCCGAGCCAGAAGTGGAGGCTGC	p.Ala1409_Glu1410insGluProGluValGluAlaAlaGluProGluValGluAlaAla	disruptive_inframe_insertion	Exon 10 of 10	1	NM_006210.3	ENSP00000326581.7
ZIM2	ENST00000629319.3	c.490+3530_490+3531insCGAGCCAGAAGTGGAGGCTGCCGAGCCAGAAGTGGAGGCTGC		intron_variant	Intron 9 of 12	5	NM_001387356.1	ENSP00000486502.2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151822 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151822 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74146

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-57325583;