X-111330994-C-A

Position:

chrX-111330994-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001195553.2(DCX):c.856G>T(p.Ala286Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,210,214 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 191 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.00050 ( 0 hom. 181 hem. )

Consequence

DCX
NM_001195553.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.87

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031125873).

BP6

Variant X-111330994-C-A is Benign according to our data. Variant chrX-111330994-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 210836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-111330994-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00033 (37/112249) while in subpopulation SAS AF= 0.00112 (3/2671). AF 95% confidence interval is 0.000389. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCX	NM_001195553.2 linkuse as main transcript	c.856G>T	p.Ala286Ser	missense_variant	5/7	ENST00000636035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCX	ENST00000636035.2 linkuse as main transcript	c.856G>T	p.Ala286Ser	missense_variant	5/7	2	NM_001195553.2	A1

Frequencies

GnomAD3 genomes

AF:

0.000330

AC:

AN:

112200

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

AN XY:

34370

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00112

Gnomad FIN

AF:

0.000327

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000399

AC:

AN:

182964

Hom.:

AF XY:

0.000474

AC XY:

AN XY:

67552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000577

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.000651

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000501

AC:

550

AN:

1097965

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

181

AN XY:

363355

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000443

Gnomad4 FIN exome

AF:

0.000222

Gnomad4 NFE exome

AF:

0.000564

Gnomad4 OTH exome

AF:

0.000759

GnomAD4 genome

AF:

0.000330

AC:

AN:

112249

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

AN XY:

34429

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00112

Gnomad4 FIN

AF:

0.000327

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000626

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 14, 2015	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	DCX: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0036

.;T;.;.;T;T;.;T;.

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.79

.;.;.;T;T;.;.;T;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.031

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.53

D;D;D;D;N

PrimateAI

Benign

0.45

PROVEAN

Benign

0.33

.;.;.;N;.;N;N;.;.

REVEL

Benign

0.020

Sift

Benign

0.44

.;.;.;T;.;T;T;.;.

Sift4G

Benign

0.54

.;.;.;T;.;T;T;.;.

Vest4

0.068, 0.056, 0.042

MVP

0.47

ClinPred

0.019

GERP RS

4.5

Varity_R

0.12

gMVP

0.30

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over