X-111301712-G-A

Position:

chrX-111301712-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001195553.2(DCX):c.1076C>T(p.Ser359Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,097,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. 4 hem. )

Failed GnomAD Quality Control

Consequence

DCX
NM_001195553.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.80

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31862146).

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCX	NM_001195553.2 linkuse as main transcript	c.1076C>T	p.Ser359Leu	missense_variant	7/7	ENST00000636035.2	NP_001182482.1	A8K340

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DCX	ENST00000636035.2 linkuse as main transcript	c.1076C>T	p.Ser359Leu	missense_variant	7/7	2	NM_001195553.2	ENSP00000490614.1	A8K340
DCX	ENST00000356220.8 linkuse as main transcript	c.1076C>T	p.Ser359Leu	missense_variant	8/8	5		ENSP00000348553.4	A8K340
DCX	ENST00000637453.1 linkuse as main transcript	c.1076C>T	p.Ser359Leu	missense_variant	7/7	5		ENSP00000490357.1	A8K340
DCX	ENST00000637570.1 linkuse as main transcript	c.1061C>T	p.Ser354Leu	missense_variant	7/7	5		ENSP00000490878.1	A0A1B0GWD1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111827

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34011

FAILED QC

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183412

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1097953

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363321

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000226

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111827

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34011

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 12, 2024

Variant summary: DCX c.1058C>T (p.Ser353Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 1204724in the gnomAD database (v4.1 dataset), including 4 hemizygotes. To our knowledge, no occurrence of c.1058C>T in individuals affected with DCX-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.024

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

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.17

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

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.32

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

MetaSVM

Benign

-0.86

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.0

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

REVEL

Benign

0.25

Sift

Benign

0.28

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

Sift4G

Benign

0.14

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

Vest4

0.56, 0.50

MVP

0.56

ClinPred

0.63

GERP RS

4.9

Varity_R

0.18

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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