rs886041068

Variant names:

• chr2-25743864-TG-T
• rs886041068
• NM_018263.6:c.2472delC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_018263.6(ASXL2):​c.2472delC​(p.Ser825ValfsTer16) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASXL2 NM_018263.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.808
• Publications: 2 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: Likely_pathogenic. The variant received 7 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. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-25743864-TG-T is Pathogenic according to our data. Variant chr2-25743864-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 268125.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018263.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL2	NM_018263.6	MANE Select	c.2472delC	p.Ser825ValfsTer16	frameshift	Exon 13 of 13	NP_060733.4
	ASXL2	NM_001369346.1		c.2298delC	p.Ser767ValfsTer16	frameshift	Exon 11 of 11	NP_001356275.1
	ASXL2	NM_001369347.1		c.1692delC	p.Ser565ValfsTer16	frameshift	Exon 10 of 10	NP_001356276.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL2	ENST00000435504.9	TSL:5 MANE Select	c.2472delC	p.Ser825ValfsTer16	frameshift	Exon 13 of 13	ENSP00000391447.3
	ASXL2	ENST00000336112.9	TSL:1	c.2469delC	p.Ser824ValfsTer16	frameshift	Exon 12 of 12	ENSP00000337250.5
	ASXL2	ENST00000404843.5	TSL:1	c.1692delC	p.Ser565ValfsTer45	frameshift	Exon 9 of 10	ENSP00000383920.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Shashi-Pena syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
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: rs886041068; hg19: chr2-25966733;