chrX-111410188-C-T

Variant names:

• chrX-111410188-C-T
• rs104894786
• NM_001195553.2:c.211G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001195553.2(DCX):​c.211G>A​(p.Ala71Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A71S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.11

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 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-111410188-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11610.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant X-111410188-C-T is Pathogenic according to our data. Variant chrX-111410188-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 812172.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2	c.211G>A	p.Ala71Thr	missense_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.211G>A	p.Ala71Thr	missense_variant	Exon 2 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.211G>A	p.Ala71Thr	missense_variant	Exon 3 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.211G>A	p.Ala71Thr	missense_variant	Exon 2 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.211G>A	p.Ala71Thr	missense_variant	Exon 2 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lissencephaly type 1 due to doublecortin gene mutation Pathogenic:1

Dec 11, 2019

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG evidence PS2, PM2, PM5, PP2, PP3 -

not provided Pathogenic:1

Jun 17, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32238909) -

Inborn genetic diseases Uncertain:1

Jul 16, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A71T variant (also known as c.211G>A), located in coding exon 1 of the DCX gene, results from a G to A substitution at nucleotide position 211. The alanine at codon 71 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	.;T;.;.;T;T;.;T;.;T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D;.;.;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	.;.;.;D;.;D;D;.;.;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0050	.;.;.;D;.;D;D;.;.;.;D
Sift4G	Uncertain	0.029	.;.;.;D;.;D;D;.;.;.;D
Vest4		0.85, 0.88, 0.88
MVP		0.99
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -26

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894786; hg19: chrX-110653416;