X-111401162-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_Moderate

The NM_001195553.2(DCX):c.533G>A(p.Arg178His) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,209,345 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R178L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

DCX
NM_001195553.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.17

Publications

2 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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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-111401162-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158473.

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, 0.804

PP5

Variant X-111401162-C-T is Pathogenic according to our data. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-111401162-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3899812.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2 link	c.533G>A	p.Arg178His	missense_variant	Exon 3 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.533G>A	p.Arg178His	missense_variant	Exon 3 of 7	2	NM_001195553.2	ENSP00000490614.1	A8K340
DCX	ENST00000356220.8 link	c.533G>A	p.Arg178His	missense_variant	Exon 4 of 8	5		ENSP00000348553.4	A8K340
DCX	ENST00000637453.1 link	c.533G>A	p.Arg178His	missense_variant	Exon 3 of 7	5		ENSP00000490357.1	A8K340
DCX	ENST00000637570.1 link	c.533G>A	p.Arg178His	missense_variant	Exon 3 of 7	5		ENSP00000490878.1	A0A1B0GWD1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111241

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000655

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

AF:

9.11e-7

AC:

AN:

1098104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30150

South Asian (SAS)

AF:

0.00

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842078

Other (OTH)

AF:

0.0000217

AC:

AN:

46088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000180

AC:

AN:

111241

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33435

show subpopulations

African (AFR)

AF:

0.0000655

AC:

AN:

30519

American (AMR)

AF:

0.00

AC:

AN:

10444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3531

South Asian (SAS)

AF:

0.00

AC:

AN:

2594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53087

Other (OTH)

AF:

0.00

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Nov 18, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Apparently de novo variant in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23365099) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

.;T;.;.;T;T;.;T;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.80

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

MetaSVM

Uncertain

0.49

PhyloP100

6.2

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.5

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

REVEL

Pathogenic

0.75

Sift

Benign

0.23

.;.;.;T;.;T;T;.;.

Sift4G

Benign

0.077

.;.;.;T;.;T;T;.;.

Vest4

0.82, 0.84, 0.84

MVP

1.0

ClinPred

0.99

GERP RS

4.7

Varity_R

0.64

gMVP

0.90

Mutation Taster

=9/91

disease causing

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over