chrX-111401162-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3PP5_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

7
5
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.17
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 7 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-111401163-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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 ClinVar 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
DCXNM_001195553.2 linkc.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 Appris UniProt
DCXENST00000636035.2 linkc.533G>A p.Arg178His missense_variant Exon 3 of 7 2 NM_001195553.2 ENSP00000490614.1 A8K340
DCXENST00000356220.8 linkc.533G>A p.Arg178His missense_variant Exon 4 of 8 5 ENSP00000348553.4 A8K340
DCXENST00000637453.1 linkc.533G>A p.Arg178His missense_variant Exon 3 of 7 5 ENSP00000490357.1 A8K340
DCXENST00000637570.1 linkc.533G>A p.Arg178His missense_variant Exon 3 of 7 5 ENSP00000490878.1 A0A1B0GWD1

Frequencies

GnomAD3 genomes
AF:
0.0000180
AC:
2
AN:
111241
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
33435
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:
1
AN:
1098104
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
363546
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
AF:
0.0000180
AC:
2
AN:
111241
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
33435
show subpopulations
Gnomad4 AFR
AF:
0.0000655
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
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
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.031
.;T;.;.;T;T;.;T;.
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
.;.;.;D;D;.;.;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.80
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.49
D
PrimateAI
Pathogenic
0.81
D
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
D
GERP RS
4.7
Varity_R
0.64
gMVP
0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587783559; hg19: chrX-110644390; COSMIC: COSV57566972; COSMIC: COSV57566972; API