chrX-111410313-G-GGGCTA

Variant names:

• chrX-111410313-G-GGGCTA
• rs797045519
• NM_001195553.2:c.81_85dupTAGCC

Variant summary

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

The NM_000555.3(DCX):​c.324_328dupTAGCC​(p.Pro110LeufsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: DCX NM_000555.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

DCX (HGNC:2714): (doublecortin) This gene encodes a member of the doublecortin family. The protein encoded by this gene is a cytoplasmic protein and contains two doublecortin domains, which bind microtubules. In the developing cortex, cortical neurons must migrate over long distances to reach the site of their final differentiation. The encoded protein appears to direct neuronal migration by regulating the organization and stability of microtubules. In addition, the encoded protein interacts with LIS1, the regulatory gamma subunit of platelet activating factor acetylhydrolase, and this interaction is important to proper microtubule function in the developing cortex. Mutations in this gene cause abnormal migration of neurons during development and disrupt the layering of the cortex, leading to epilepsy, cognitive disability, subcortical band heterotopia ("double cortex" syndrome) in females and lissencephaly ("smooth brain" syndrome) in males. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2010]

DCX Gene-Disease associations (from GenCC):

• lissencephaly spectrum disorders

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• lissencephaly type 1 due to doublecortin gene mutation

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• subcortical band heterotopia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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 X-111410313-G-GGGCTA is Pathogenic according to our data. Variant chrX-111410313-G-GGGCTA is described in ClinVar as Pathogenic. ClinVar VariationId is 210835.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000555.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCX	NM_001195553.2	MANE Select	c.81_85dupTAGCC	p.Pro29LeufsTer20	frameshift	Exon 2 of 7	NP_001182482.1
	DCX	NM_000555.3		c.324_328dupTAGCC	p.Pro110LeufsTer20	frameshift	Exon 2 of 7	NP_000546.2
	DCX	NM_001369370.1		c.81_85dupTAGCC	p.Pro29LeufsTer20	frameshift	Exon 2 of 7	NP_001356299.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCX	ENST00000636035.2	TSL:2 MANE Select	c.81_85dupTAGCC	p.Pro29LeufsTer20	frameshift	Exon 2 of 7	ENSP00000490614.1
	DCX	ENST00000358070.10	TSL:1	c.261_265dupTAGCC	p.Pro89LeufsTer20	frameshift	Exon 2 of 7	ENSP00000350776.6
	DCX	ENST00000356220.8	TSL:5	c.81_85dupTAGCC	p.Pro29LeufsTer20	frameshift	Exon 3 of 8	ENSP00000348553.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal cortical gyration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797045519; hg19: chrX-110653541;