X-111401138-C-T

Position:

• chrX-111401138-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001195553.2(DCX):​c.557G>A​(p.Arg186His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 6.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant X-111401138-C-T is Pathogenic according to our data. Variant chrX-111401138-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158477.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCX	NM_001195553.2	c.557G>A	p.Arg186His	missense_variant	3/7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.557G>A	p.Arg186His	missense_variant	3/7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.557G>A	p.Arg186His	missense_variant	4/8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.557G>A	p.Arg186His	missense_variant	3/7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.557G>A	p.Arg186His	missense_variant	3/7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000496 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ectopic tissue Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25326635, 17111359, 31481326, 23365099) -

Lissencephaly type 1 due to doublecortin gene mutation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

This variant has been previously reported in single individual with no family, population, or functional studies. It was identified once in our laboratory de novo in a 12-year-old female with Lennox-Gastaut epilepsy, static encephalopathy, band heterotopia/double cortex on brain imaging, global delays, scoliosis. -

Seizure Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	.;T;.;.;T;T;.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;.;.;D;D;.;.;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.9	.;.;.;D;.;D;D;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;.;.;D;.;D;D;.;.
Sift4G	Uncertain	0.0050	.;.;.;D;.;D;D;.;.
Vest4		0.90, 0.95, 0.96
MVP		1.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.93
gMVP		0.97

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

Other links and lift over

dbSNP: rs587783563; hg19: chrX-110644366;