rs886041065

Positions:

• chr2-25743912-TG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_018263.6(ASXL2):​c.2424del​(p.Thr809ProfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASXL2 NM_018263.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.490

Genes affected

ASXL2 (HGNC:23805): (ASXL transcriptional regulator 2) This gene encodes a member of a family of epigenetic regulators that bind various histone-modifying enzymes and are involved in the assembly of transcription factors at specific genomic loci. Naturally occurring mutations in this gene are associated with cancer in several tissue types (breast, bladder, pancreas, ovary, prostate, and blood). This gene plays an important role in neurodevelopment, cardiac function, adipogenesis, and osteoclastogenesis. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.437 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-25743912-TG-T is Pathogenic according to our data. Variant chr2-25743912-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 268122.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL2	NM_018263.6	c.2424del	p.Thr809ProfsTer32	frameshift_variant	13/13	ENST00000435504.9	NP_060733.4
ASXL2	NM_001369346.1	c.2250del	p.Thr751ProfsTer32	frameshift_variant	11/11		NP_001356275.1
ASXL2	NM_001369347.1	c.1644del	p.Thr549ProfsTer32	frameshift_variant	10/10		NP_001356276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL2	ENST00000435504.9	c.2424del	p.Thr809ProfsTer32	frameshift_variant	13/13	5	NM_018263.6	ENSP00000391447	P4
ASXL2	ENST00000336112.9	c.2421del	p.Thr808ProfsTer32	frameshift_variant	12/12	1		ENSP00000337250	A2
ASXL2	ENST00000404843.5	c.1644del	p.Thr549ProfsTer61	frameshift_variant	9/10	1		ENSP00000383920	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Shashi-Pena syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jan 16, 2017	This patient has been reported in PMID 27693232. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 11, 2016	- -

Computational scores

Source: dbNSFP v4.3

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: rs886041065; hg19: chr2-25966781;