NM_018263.6:c.1288G>T

Variant names:

• chr2-25750268-C-A
• rs886041070
• NM_018263.6:c.1288G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018263.6(ASXL2):​c.1288G>T​(p.Glu430*) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASXL2 NM_018263.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.48
• Publications: 4 publications found

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]

ASXL2 Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Shashi-Pena syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 VariationId is 268127.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASXL2	NM_018263.6	c.1288G>T	p.Glu430*	stop_gained	Exon 12 of 13	ENST00000435504.9	NP_060733.4
ASXL2	NM_001369346.1	c.1114G>T	p.Glu372*	stop_gained	Exon 10 of 11		NP_001356275.1
ASXL2	NM_001369347.1	c.508G>T	p.Glu170*	stop_gained	Exon 9 of 10		NP_001356276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASXL2	ENST00000435504.9	c.1288G>T	p.Glu430*	stop_gained	Exon 12 of 13	5	NM_018263.6	ENSP00000391447.3
ASXL2	ENST00000336112.9	c.1285G>T	p.Glu429*	stop_gained	Exon 11 of 12	1		ENSP00000337250.5
ASXL2	ENST00000404843.5	c.508G>T	p.Glu170*	stop_gained	Exon 8 of 10	1		ENSP00000383920.1
ASXL2	ENST00000673455.1	c.508G>T	p.Glu170*	stop_gained	Exon 9 of 10			ENSP00000500467.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Shashi-Pena syndrome Pathogenic:2

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		3.5
Vest4		0.93
GERP RS		4.9
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041070; hg19: chr2-25973137;