rs201805884

Positions:

• chrX-111400942-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195553.2(DCX):​c.705+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,105,353 control chromosomes in the GnomAD database, including 94 homozygotes. There are 4,095 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (16 hom., 295 hem., cov: 23)
  • Exomes 𝑓: 0.011 (78 hom. 3800 hem.)
• Consequence: DCX NM_001195553.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.840

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-111400942-T-C is Benign according to our data. Variant chrX-111400942-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 262926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-111400942-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00891 (1001/112359) while in subpopulation SAS AF= 0.0288 (77/2670). AF 95% confidence interval is 0.0237. There are 16 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCX	NM_001195553.2	c.705+48A>G		intron_variant		ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.705+48A>G		intron_variant		2	NM_001195553.2	ENSP00000490614	A1

Frequencies

GnomAD3 genomes AF: 0.00893 AC: 1003 AN: 112307 Hom.: 16 Cov.: 23 AF XY: 0.00859 AC XY: 296 AN XY: 34465

Gnomad AFR AF: 0.00120

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.00377

Gnomad ASJ AF: 0.0290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0291

Gnomad FIN AF: 0.00553

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.0109 AC: 1918 AN: 176182 Hom.: 22 AF XY: 0.0128 AC XY: 818 AN XY: 63886

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.0000734

Gnomad SAS exome AF: 0.0335

Gnomad FIN exome AF: 0.00548

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.0113 AC: 11232 AN: 992994 Hom.: 78 Cov.: 19 AF XY: 0.0130 AC XY: 3800 AN XY: 293388

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.0257

Gnomad4 EAS exome AF: 0.0000674

Gnomad4 SAS exome AF: 0.0332

Gnomad4 FIN exome AF: 0.00681

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00891 AC: 1001 AN: 112359 Hom.: 16 Cov.: 23 AF XY: 0.00854 AC XY: 295 AN XY: 34527

Gnomad4 AFR AF: 0.00119

Gnomad4 AMR AF: 0.00376

Gnomad4 ASJ AF: 0.0290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.00553

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.0107 Hom.: 81

Bravo AF: 0.00832

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2018	This variant is associated with the following publications: (PMID: 28492530, 27884173, 12390976) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.47
DANN	Benign	0.34

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: rs201805884; hg19: chrX-110644170;