X-111400942-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001195553.2(DCX):c.705+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,105,353 control chromosomes in the GnomAD database, including 94 homozygotes. There are 4,095 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 16 hom., 295 hem., cov: 23)

Exomes 𝑓: 0.011 ( 78 hom. 3800 hem. )

Consequence

DCX
NM_001195553.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.840

Publications

0 publications found

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 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

DCX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant X-111400942-T-C is Benign according to our data. Variant chrX-111400942-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 262926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00891 (1001/112359) while in subpopulation SAS AF = 0.0288 (77/2670). AF 95% confidence interval is 0.0237. There are 16 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2 link	c.705+48A>G		intron_variant	Intron 3 of 6	ENST00000636035.2	NP_001182482.1	A8K340

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DCX	ENST00000636035.2 link	c.705+48A>G	intron_variant	Intron 3 of 6	2	NM_001195553.2	ENSP00000490614.1	A8K340
DCX	ENST00000356220.8 link	c.705+48A>G	intron_variant	Intron 4 of 7	5		ENSP00000348553.4	A8K340
DCX	ENST00000637453.1 link	c.705+48A>G	intron_variant	Intron 3 of 6	5		ENSP00000490357.1	A8K340
DCX	ENST00000637570.1 link	c.705+48A>G	intron_variant	Intron 3 of 6	5		ENSP00000490878.1	A0A1B0GWD1

Frequencies

GnomAD3 genomes

AF:

0.00893

AC:

1003

AN:

112307

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00120

Gnomad AMI

AF:

0.196

Gnomad AMR

AF:

0.00377

Gnomad ASJ

AF:

0.0290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0291

Gnomad FIN

AF:

0.00553

Gnomad MID

AF:

0.0210

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.00863

GnomAD2 exomes

AF:

0.0109

AC:

1918

AN:

176182

AF XY:

0.0128

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.0260

Gnomad EAS exome

AF:

0.0000734

Gnomad FIN exome

AF:

0.00548

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0141

GnomAD4 exome

AF:

0.0113

AC:

11232

AN:

992994

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

3800

AN XY:

293388

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

24350

American (AMR)

AF:

0.00286

AC:

100

AN:

35000

Ashkenazi Jewish (ASJ)

AF:

0.0257

AC:

482

AN:

18722

East Asian (EAS)

AF:

0.0000674

AC:

AN:

29687

South Asian (SAS)

AF:

0.0332

AC:

1716

AN:

51739

European-Finnish (FIN)

AF:

0.00681

AC:

269

AN:

39494

Middle Eastern (MID)

AF:

0.0220

AC:

AN:

3871

European-Non Finnish (NFE)

AF:

0.0108

AC:

8068

AN:

747500

Other (OTH)

AF:

0.0113

AC:

483

AN:

42631

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

383

767

1150

1534

1917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

296

592

888

1184

1480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00891

AC:

1001

AN:

112359

Hom.:

Cov.:

AF XY:

0.00854

AC XY:

295

AN XY:

34527

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

30977

American (AMR)

AF:

0.00376

AC:

AN:

10633

Ashkenazi Jewish (ASJ)

AF:

0.0290

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3583

South Asian (SAS)

AF:

0.0288

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.00553

AC:

AN:

6143

Middle Eastern (MID)

AF:

0.0184

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0110

AC:

586

AN:

53278

Other (OTH)

AF:

0.00852

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.00832

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 17, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Sep 29, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28492530, 27884173, 12390976) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.47

(source)

DANN

Benign

0.34

PhyloP100

-0.84

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over