rs104894784

Positions:

• chrX-111410166-C-A
• chrX-111410166-C-T

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.233G>T​(p.Arg78Leu) 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:4
• Conservation: PhyloP100: 7.91

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, 0.935
• PP5: Variant X-111410166-C-A is Pathogenic according to our data. Variant chrX-111410166-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 158443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-111410166-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.233G>T	p.Arg78Leu	missense_variant	2/7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.233G>T	p.Arg78Leu	missense_variant	2/7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.233G>T	p.Arg78Leu	missense_variant	3/8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.233G>T	p.Arg78Leu	missense_variant	2/7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.233G>T	p.Arg78Leu	missense_variant	2/7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly type 1 due to doublecortin gene mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Oct 02, 2021

Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in a similarly affected individual (PMID: 29671837, PS2) The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg78Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000158442.1, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.956, 3Cnet: 0.996, PP3). Patient's phenotype is considered compatible with Ayme-Gripp syndrome (3billion dataset, PP4).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Ectopic tissue Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Lissencephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 13, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9668176, 29671837, 30352490, 23365099, 10770842, 11175293) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;D;.;.;T;D;.;D;.;T;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;.;.;D;D;.;.;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.9	.;.;.;D;.;D;D;.;.;.;D
REVEL	Pathogenic	0.96
Sift	Benign	0.033	.;.;.;D;.;D;D;.;.;.;T
Sift4G	Uncertain	0.033	.;.;.;D;.;D;D;.;.;.;T
Vest4		0.95, 0.96, 0.97
MVP		0.99
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.95

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: rs104894784; hg19: chrX-110653394;