chrX-111410094-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5

The NM_001195553.2(DCX):c.305G>A(p.Arg102His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 22)

Failed GnomAD Quality Control

Consequence

DCX
NM_001195553.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.91

Publications

5 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: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001195553.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-111410095-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158452.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

PP5

Variant X-111410094-C-T is Pathogenic according to our data. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052. Variant chrX-111410094-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 82052.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2 link	c.305G>A	p.Arg102His	missense_variant	Exon 2 of 7	ENST00000636035.2	NP_001182482.1	A8K340

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DCX	ENST00000636035.2 link	c.305G>A	p.Arg102His	missense_variant	Exon 2 of 7	2	NM_001195553.2	ENSP00000490614.1	A8K340
DCX	ENST00000356220.8 link	c.305G>A	p.Arg102His	missense_variant	Exon 3 of 8	5		ENSP00000348553.4	A8K340
DCX	ENST00000637453.1 link	c.305G>A	p.Arg102His	missense_variant	Exon 2 of 7	5		ENSP00000490357.1	A8K340
DCX	ENST00000637570.1 link	c.305G>A	p.Arg102His	missense_variant	Exon 2 of 7	5		ENSP00000490878.1	A0A1B0GWD1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111935

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111935

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34109

African (AFR)

AF:

0.00

AC:

AN:

30751

American (AMR)

AF:

0.00

AC:

AN:

10555

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6101

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53255

Other (OTH)

AF:

0.00

AC:

AN:

1489

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ectopic tissue

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lissencephaly type 1 due to doublecortin gene mutation

Uncertain:1

Oct 15, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.69

BayesDel_noAF

Pathogenic

0.76

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

.;D;.;.;T;D;.;D;.;T;D

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

.;.;.;D;D;.;.;D;D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.061

PhyloP100

7.9

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.3

.;.;.;D;.;D;D;.;.;.;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;.;.;D;.;D;D;.;.;.;D

Sift4G

Pathogenic

0.0

.;.;.;D;.;D;D;.;.;.;D

Vest4

0.98, 0.97

MVP

1.0

ClinPred

1.0

GERP RS

5.5

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.98

gMVP

0.97

Mutation Taster

=1/99

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over