NM_001195553.2:c.586C>A

Variant names:

• chrX-111401109-G-T
• rs587783568
• NM_001195553.2:c.586C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001195553.2(DCX):​c.586C>A​(p.Arg196Ser) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.63
• Publications: 4 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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-111401109-G-A is described in CliVar as Pathogenic. Clinvar id is 158485.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, 0.917
• PP5: Variant X-111401109-G-T is Pathogenic according to our data. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483. Variant chrX-111401109-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158483.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2	c.586C>A	p.Arg196Ser	missense_variant	Exon 3 of 7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.586C>A	p.Arg196Ser	missense_variant	Exon 3 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.586C>A	p.Arg196Ser	missense_variant	Exon 4 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.586C>A	p.Arg196Ser	missense_variant	Exon 3 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.586C>A	p.Arg196Ser	missense_variant	Exon 3 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000849 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ectopic tissue Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Apr 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with lissencephaly (PMID: 12027577). ClinVar contains an entry for this variant (Variation ID: 158483). 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 variant disrupts the p.Arg196 amino acid residue in DCX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11468322, 18685874). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 196 of the DCX protein (p.Arg196Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.;.;T;T;.;T;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D;.;.;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
PhyloP100		5.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	.;.;.;D;.;D;D;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	.;.;.;D;.;D;D;.;.
Sift4G	Uncertain	0.034	.;.;.;D;.;D;D;.;.
Vest4		0.94, 0.93
MVP		1.0
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783568; hg19: chrX-110644337;