NM_018263.6:c.1225_1228delCCAA

Variant names:

• chr2-25750327-TTTGG-T
• rs886041067
• NM_018263.6:c.1225_1228delCCAA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_018263.6(ASXL2):​c.1225_1228delCCAA​(p.Pro409AsnfsTer13) 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). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASXL2 NM_018263.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.25
• 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: Pathogenic. The variant received 11 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 2-25750327-TTTGG-T is Pathogenic according to our data. Variant chr2-25750327-TTTGG-T is described in ClinVar as [Pathogenic]. Clinvar id is 268124.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASXL2	NM_018263.6	c.1225_1228delCCAA	p.Pro409AsnfsTer13	frameshift_variant	Exon 12 of 13	ENST00000435504.9	NP_060733.4
ASXL2	NM_001369346.1	c.1051_1054delCCAA	p.Pro351AsnfsTer13	frameshift_variant	Exon 10 of 11		NP_001356275.1
ASXL2	NM_001369347.1	c.445_448delCCAA	p.Pro149AsnfsTer13	frameshift_variant	Exon 9 of 10		NP_001356276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASXL2	ENST00000435504.9	c.1225_1228delCCAA	p.Pro409AsnfsTer13	frameshift_variant	Exon 12 of 13	5	NM_018263.6	ENSP00000391447.3
ASXL2	ENST00000336112.9	c.1222_1225delCCAA	p.Pro408AsnfsTer13	frameshift_variant	Exon 11 of 12	1		ENSP00000337250.5
ASXL2	ENST00000404843.5	c.445_448delCCAA	p.Pro149AsnfsTer13	frameshift_variant	Exon 8 of 10	1		ENSP00000383920.1
ASXL2	ENST00000673455.1	c.445_448delCCAA	p.Pro149AsnfsTer13	frameshift_variant	Exon 9 of 10			ENSP00000500467.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Shashi-Pena syndrome Pathogenic:1

Nov 11, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
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: rs886041067; hg19: chr2-25973196;