X-111333108-C-A

Position:

• chrX-111333108-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001195553.2(DCX):​c.751G>T​(p.Ala251Ser) 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, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.90

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant X-111333108-C-A is Pathogenic according to our data. Variant chrX-111333108-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 158504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-111333108-C-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCX	NM_001195553.2	c.751G>T	p.Ala251Ser	missense_variant	4/7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.751G>T	p.Ala251Ser	missense_variant	4/7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.751G>T	p.Ala251Ser	missense_variant	5/8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.751G>T	p.Ala251Ser	missense_variant	4/7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.751G>T	p.Ala251Ser	missense_variant	4/7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 02, 2021

This sequence change replaces alanine with serine at codon 251 of the DCX protein (p.Ala251Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala251 amino acid residue in DCX. Other variant(s) that disrupt this residue have been observed in individuals with DCX-related conditions (PMID: 10807542, 11175293, 28953922; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 158504). This variant has been observed in individual(s) with lissencephaly and subcortical band heterotopia (PMID: 11175293; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;D;.;.;T;D;.;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D;.;.;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	.;.;.;N;.;N;N;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	.;.;.;D;.;D;D;.;.
Sift4G	Uncertain	0.010	.;.;.;D;.;D;D;.;.
Vest4		0.94, 0.94, 0.95
MVP		1.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.94

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: rs587783585; hg19: chrX-110576336;