rs886041070

Positions:

• chr2-25750268-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_018263.6(ASXL2):​c.1288G>T​(p.Glu430Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASXL2 NM_018263.6 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.48

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 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.701 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-25750268-C-A is Pathogenic according to our data. Variant chr2-25750268-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 268127.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL2	NM_018263.6	c.1288G>T	p.Glu430Ter	stop_gained	12/13	ENST00000435504.9	NP_060733.4
ASXL2	NM_001369346.1	c.1114G>T	p.Glu372Ter	stop_gained	10/11		NP_001356275.1
ASXL2	NM_001369347.1	c.508G>T	p.Glu170Ter	stop_gained	9/10		NP_001356276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL2	ENST00000435504.9	c.1288G>T	p.Glu430Ter	stop_gained	12/13	5	NM_018263.6	ENSP00000391447	P4
ASXL2	ENST00000336112.9	c.1285G>T	p.Glu429Ter	stop_gained	11/12	1		ENSP00000337250	A2
ASXL2	ENST00000404843.5	c.508G>T	p.Glu170Ter	stop_gained	8/10	1		ENSP00000383920	A2
ASXL2	ENST00000673455.1	c.508G>T	p.Glu170Ter	stop_gained	9/10			ENSP00000500467

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Shashi-Pena syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.93
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs886041070; hg19: chr2-25973137;