rs587783519

Positions:

• chrX-111410284-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001195553.2(DCX):​c.115C>T​(p.Arg39*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,189 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DCX NM_001195553.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.14

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-111410284-G-A is Pathogenic according to our data. Variant chrX-111410284-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 158425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCX	NM_001195553.2	c.115C>T	p.Arg39*	stop_gained	2/7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.115C>T	p.Arg39*	stop_gained	2/7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.115C>T	p.Arg39*	stop_gained	3/8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.115C>T	p.Arg39*	stop_gained	2/7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.115C>T	p.Arg39*	stop_gained	2/7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098189 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363587

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2022

The c.115C>T (p.R39*) alteration, located in exon 2 (coding exon 1) of the DCX gene, consists of a C to T substitution at nucleotide position 115. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 39. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in multiple female patients with DCX-related lissencephaly (Des Portes, 1998; Spencer-Smith, 2009), including as a de novo event in multiple unrelated female patients with subcortical band heterotopia (Bahi-Buisson, 2013). In a yeast two-hybrid assay, the p.R39* alteration was shown to cause a complete loss of binding to neurabin II, a protein that is critical for DCX function (Tsukada, 2003). Based on the available evidence, this alteration is classified as pathogenic. -

Lissencephaly type 1 due to doublecortin gene mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Human Genetics, Hannover Medical School

Sep 04, 2024

- -

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

Oct 04, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 158425). This premature translational stop signal has been observed in individual(s) with subcortical band heterotopia (PMID: 9618162). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg39*) in the DCX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCX are known to be pathogenic (PMID: 11175293, 23365099). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.94, 0.94, 0.94
GERP RS		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587783519; hg19: chrX-110653512; COSMIC: COSV57571382;