rs587783541

Variant names:

• chrX-111410095-G-A
• rs587783541
• NM_001195553.2:c.304C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-111410095-G-A
• chrX-111410095-G-C
• chrX-111410095-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001195553.2(DCX):​c.304C>T​(p.Arg102Cys) 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. R102H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.70
• Publications: 7 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 12 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, 2 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-111410095-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1320092.Status of the report is criteria_provided_single_submitter, 1 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, 0.944
• PP5: Variant X-111410095-G-A is Pathogenic according to our data. Variant chrX-111410095-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158452.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2	c.304C>T	p.Arg102Cys	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.304C>T	p.Arg102Cys	missense_variant	Exon 2 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.304C>T	p.Arg102Cys	missense_variant	Exon 3 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.304C>T	p.Arg102Cys	missense_variant	Exon 2 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.304C>T	p.Arg102Cys	missense_variant	Exon 2 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 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

Oct 11, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant appears to occur de novo in one individual with lissencephaly. In some published literature, this variant is referred to as R102C. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;D;.;.;D;D;.;D;.;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;.;.;D;D;.;.;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		6.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.8	.;.;.;D;.;D;D;.;.;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;.;D;.;D;D;.;.;.;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;D;D;.;.;.;D
Vest4		0.97, 0.98, 0.98
MVP		1.0
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.045	Neutral
Varity_R		0.99
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: rs587783541; hg19: chrX-110653323; COSMIC: COSV57565978;