X-111410173-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate

The NM_001195553.2(DCX):c.226C>A(p.Arg76Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,177 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

DCX
NM_001195553.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.52

Publications

3 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_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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-111410173-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 158441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2 link	c.226C>A	p.Arg76Ser	missense_variant	Exon 2 of 7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DCX	ENST00000636035.2 link	c.226C>A	p.Arg76Ser	missense_variant	Exon 2 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8 link	c.226C>A	p.Arg76Ser	missense_variant	Exon 3 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1 link	c.226C>A	p.Arg76Ser	missense_variant	Exon 2 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1 link	c.226C>A	p.Arg76Ser	missense_variant	Exon 2 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183065

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098177

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363577

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30182

South Asian (SAS)

AF:

0.00

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842102

Other (OTH)

AF:

0.00

AC:

AN:

46092

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000308

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

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

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.0

.;.;.;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

0.79

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.

PhyloP100

5.5

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.0

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

REVEL

Benign

0.0

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.0

ClinPred

0.95

GERP RS

5.5

PromoterAI

-0.061

Neutral

(source)

Varity_R

0.99

gMVP

0.97

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Computational scores

Splicing

Publications

Other links and lift over