Genetic Variant DCX:p.Pro43Leu (chrX-111410784-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PP2PP5_ModerateBP4BS2

The ENST00000358070.10(DCX):c.128C>T(p.Pro43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,208,031 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 6/8 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000020 ( 0 hom. 5 hem. )

Consequence

DCX
ENST00000358070.10 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1B:1

Conservation

PhyloP100: -0.524

Publications

1 publications found

Variant links:

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

DCX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 87 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to lissencephaly type 1 due to doublecortin gene mutation, lissencephaly spectrum disorders, subcortical band heterotopia.

PP5

Variant X-111410784-G-A is Pathogenic according to our data. Variant chrX-111410784-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 495232.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (REVEL=0.106). . Strength limited to SUPPORTING due to the PP5.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000358070.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DCX	NM_001195553.2	MANE Select	c.-22-364C>T		intron	N/A	NP_001182482.1
DCX	NM_000555.3		c.191C>T	p.Pro64Leu	missense	Exon 1 of 7	NP_000546.2
DCX	NM_001369370.1		c.-22-364C>T		intron	N/A	NP_001356299.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DCX	ENST00000358070.10	TSL:1	c.128C>T	p.Pro43Leu	missense	Exon 1 of 7	ENSP00000350776.6
DCX	ENST00000636035.2	TSL:2 MANE Select	c.-22-364C>T		intron	N/A	ENSP00000490614.1
DCX	ENST00000356220.8	TSL:5	c.-22-364C>T		intron	N/A	ENSP00000348553.4

Frequencies

GnomAD3 genomes

AF:

0.0000272

AC:

AN:

110198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000568

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000327

AC:

AN:

183364

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1097833

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363267

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26388

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30196

South Asian (SAS)

AF:

0.00

AC:

AN:

54141

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000238

AC:

AN:

841770

Other (OTH)

AF:

0.0000434

AC:

AN:

46084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000272

AC:

AN:

110198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30214

American (AMR)

AF:

0.00

AC:

AN:

10288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2625

East Asian (EAS)

AF:

0.00

AC:

AN:

3494

South Asian (SAS)

AF:

0.00

AC:

AN:

2527

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000568

AC:

AN:

52845

Other (OTH)

AF:

0.00

AC:

AN:

1472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000302

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lissencephaly type 1 due to doublecortin gene mutation

Pathogenic:1Benign:1

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 01, 2018

NeuroMeGen, Hospital Clinico Santiago de Compostela

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.6

(source)

DANN

Benign

0.89

PhyloP100

-0.52

PromoterAI

0.056

Neutral

(source)

Mutation Taster

=99/1

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over