rs201805884

Variant names:

• chrX-111400942-T-C
• rs201805884
• NM_001195553.2:c.705+48A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 262926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195553.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCX	NM_001195553.2	MANE Select	c.705+48A>G		intron	N/A	NP_001182482.1	A8K340
	DCX	NM_000555.3		c.948+48A>G		intron	N/A	NP_000546.2	O43602
	DCX	NM_001369370.1		c.705+48A>G		intron	N/A	NP_001356299.1	A8K340

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCX	ENST00000636035.2	TSL:2 MANE Select	c.705+48A>G		intron	N/A	ENSP00000490614.1	A8K340
	DCX	ENST00000358070.10	TSL:1	c.885+48A>G		intron	N/A	ENSP00000350776.6	A0A9S7JGE9
	DCX	ENST00000356220.8	TSL:5	c.705+48A>G		intron	N/A	ENSP00000348553.4	A8K340

Frequencies

GnomAD3 genomes AF: 0.00893 AC: 1003 AN: 112307 Hom.: 16 Cov.: 23

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

GnomAD2 exomes AF: 0.0109 AC: 1918 AN: 176182 AF XY: 0.0128

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 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

African (AFR) AF: 0.00111 AC: 27 AN: 24350

American (AMR) AF: 0.00286 AC: 100 AN: 35000

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 482 AN: 18722

East Asian (EAS) AF: 0.0000674 AC: 2 AN: 29687

South Asian (SAS) AF: 0.0332 AC: 1716 AN: 51739

European-Finnish (FIN) AF: 0.00681 AC: 269 AN: 39494

Middle Eastern (MID) AF: 0.0220 AC: 85 AN: 3871

European-Non Finnish (NFE) AF: 0.0108 AC: 8068 AN: 747500

Other (OTH) AF: 0.0113 AC: 483 AN: 42631

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

African (AFR) AF: 0.00119 AC: 37 AN: 30977

American (AMR) AF: 0.00376 AC: 40 AN: 10633

Ashkenazi Jewish (ASJ) AF: 0.0290 AC: 77 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.0288 AC: 77 AN: 2670

European-Finnish (FIN) AF: 0.00553 AC: 34 AN: 6143

Middle Eastern (MID) AF: 0.0184 AC: 4 AN: 217

European-Non Finnish (NFE) AF: 0.0110 AC: 586 AN: 53278

Other (OTH) AF: 0.00852 AC: 13 AN: 1526

Alfa AF: 0.0107 Hom.: 81

Bravo AF: 0.00832

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.47
DANN	Benign	0.34
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201805884;

hg19: chrX-110644170;