rs104894783

Variant names:

• chrX-111410260-T-G
• rs104894783
• NM_001195553.2:c.139A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001195553.2(DCX):​c.139A>C​(p.Ser47Arg) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: DCX NM_001195553.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 6.17

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2	c.139A>C	p.Ser47Arg	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.139A>C	p.Ser47Arg	missense_variant	Exon 2 of 7	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.139A>C	p.Ser47Arg	missense_variant	Exon 3 of 8	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.139A>C	p.Ser47Arg	missense_variant	Exon 2 of 7	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.139A>C	p.Ser47Arg	missense_variant	Exon 2 of 7	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly type 1 due to doublecortin gene mutation Pathogenic:1

Jan 09, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Subcortical laminar heterotopia, X-linked Pathogenic:1

Jan 09, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Nov 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with lissencephaly and subcortical band heterotopia (PMID: 9489700). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 47 of the DCX protein (p.Ser47Arg). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 11603). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects DCX function (PMID: 10749977, 11331616, 22857951). This variant disrupts the p.Ser47 amino acid residue in DCX. Other variant(s) that disrupt this residue have been observed in individuals with DCX-related conditions (PMID: 9489700, 23365099), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	.;T;.;.;T;T;.;T;.;T;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	.;.;.;D;D;.;.;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.80	T
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	.;.;.;D;.;D;D;.;.;.;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	.;.;.;D;.;D;D;.;.;.;D
Sift4G	Uncertain	0.0040	.;.;.;D;.;D;D;.;.;.;D
Vest4		0.60, 0.65, 0.68
MVP		1.0
ClinPred		0.94	D
GERP RS		4.2
Varity_R		0.91
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs104894783; hg19: chrX-110653488;