chrX-111410035-C-T

Variant names:

• chrX-111410035-C-T
• rs587783544
• NM_001195553.2:c.364G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001195553.2(DCX):​c.364G>A​(p.Gly122Arg) variant causes a missense, splice region 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. 15/24 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G122G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DCX NM_001195553.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.91
• Publications: 1 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 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001195553.2
• PM2: Very rare variant in population databases, with high coverage
• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-111410035-C-T is Pathogenic according to our data. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456. Variant chrX-111410035-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158456.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2	c.364G>A	p.Gly122Arg	missense_variant, splice_region_variant	Exon 2 of 7	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.364G>A	p.Gly122Arg	missense_variant, splice_region_variant	Exon 2 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.364G>A	p.Gly122Arg	missense_variant, splice_region_variant	Exon 3 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.364G>A	p.Gly122Arg	missense_variant, splice_region_variant	Exon 2 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.364G>A	p.Gly122Arg	missense_variant, splice_region_variant	Exon 2 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ectopic tissue Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jun 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with lissencephaly (Invitae). ClinVar contains an entry for this variant (Variation ID: 158456). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Gly122 amino acid residue in DCX. Other variant(s) that disrupt this residue have been observed in individuals with DCX-related conditions (PMID: 17111359), which suggests that this may be a clinically significant amino acid residue. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 122 of the DCX protein (p.Gly122Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	.;D;.;.;T;D;.;D;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D;.;.;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.4	.;.;.;D;.;D;D;.;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	.;.;.;D;.;D;D;.;.;.
Sift4G	Uncertain	0.0060	.;.;.;D;.;D;D;.;.;.
Vest4		0.93, 0.94, 0.94
MVP		0.99
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.23	Neutral
Varity_R		0.96
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.52		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587783544; hg19: chrX-110653263;