rs386576624

Variant names:

• chrX-111401108-C-T
• rs56030372
• NM_001195553.2:c.587G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-111401108-C-T
• chrX-111401108-C-A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001195553.2(DCX):​c.587G>A​(p.Arg196His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 111,607 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196S) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.91
• Publications: 11 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001195553.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-111401109-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158483.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 87 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to lissencephaly type 1 due to doublecortin gene mutation, lissencephaly spectrum disorders, subcortical band heterotopia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant X-111401108-C-T is Pathogenic according to our data. Variant chrX-111401108-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCX	NM_001195553.2	MANE Select	c.587G>A	p.Arg196His	missense	Exon 3 of 7	NP_001182482.1
	DCX	NM_000555.3		c.830G>A	p.Arg277His	missense	Exon 3 of 7	NP_000546.2
	DCX	NM_001369370.1		c.587G>A	p.Arg196His	missense	Exon 3 of 7	NP_001356299.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCX	ENST00000636035.2	TSL:2 MANE Select	c.587G>A	p.Arg196His	missense	Exon 3 of 7	ENSP00000490614.1
	DCX	ENST00000358070.10	TSL:1	c.767G>A	p.Arg256His	missense	Exon 3 of 7	ENSP00000350776.6
	DCX	ENST00000356220.8	TSL:5	c.587G>A	p.Arg196His	missense	Exon 4 of 8	ENSP00000348553.4

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111607 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111607 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33779

African (AFR) AF: 0.00 AC: 0 AN: 30659

American (AMR) AF: 0.00 AC: 0 AN: 10470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2630

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6033

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53188

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Lissencephaly type 1 due to doublecortin gene mutation (2)
2	-	-	not provided (2)
-	1	-	Abnormal cerebral morphology (1)
1	-	-	Ectopic tissue (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Subcortical laminar heterotopia, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.16	T
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Vest4		0.90
MVP		1.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs56030372; hg19: chrX-110644336; COSMIC: COSV57566600; COSMIC: COSV57566600;