rs1556405129

Variant names:

• chrX-111410209-A-C
• NM_001195553.2:c.190T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-111410209-A-C
• chrX-111410209-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001195553.2(DCX):​c.190T>G​(p.Tyr64Asp) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant X-111410209-A-C is Pathogenic according to our data. Variant chrX-111410209-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2811793.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	c.190T>G	p.Tyr64Asp	missense_variant	Exon 2 of 7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.190T>G	p.Tyr64Asp	missense_variant	Exon 2 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.190T>G	p.Tyr64Asp	missense_variant	Exon 3 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.190T>G	p.Tyr64Asp	missense_variant	Exon 2 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.190T>G	p.Tyr64Asp	missense_variant	Exon 2 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr64 amino acid residue in DCX. Other variant(s) that disrupt this residue have been observed in individuals with DCX-related conditions (PMID: 18685874, 29706646; Invitae), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DCX protein function. This missense change has been observed in individual(s) with lissencephaly (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 64 of the DCX protein (p.Tyr64Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;T;.;.;T;T;.;T;.;T;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;D;D;.;.;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.3	.;.;.;D;.;D;D;.;.;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	.;.;.;D;.;D;D;.;.;.;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;D;D;.;.;.;D
Vest4		0.75, 0.73, 0.72
MVP		1.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-110653437;