rs149495971

Positions:

• chrX-111330994-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.87

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 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	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	c.856G>T	p.Ala286Ser	missense_variant	5/7	2	NM_001195553.2	A1

Frequencies

GnomAD3 genomes AF: 0.000330 AC: 37 AN: 112200 Hom.: 0 Cov.: 23 AF XY: 0.000291 AC XY: 10 AN XY: 34370

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: 73 AN: 182964 Hom.: 0 AF XY: 0.000474 AC XY: 32 AN XY: 67552

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.: 0 Cov.: 31 AF XY: 0.000498 AC XY: 181 AN XY: 363355

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: 37 AN: 112249 Hom.: 0 Cov.: 23 AF XY: 0.000290 AC XY: 10 AN XY: 34429

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.: 20

Bravo AF: 0.000374

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000600

EpiControl AF: 0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	21
DANN	Benign	0.97
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.031	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.53	D;D;D;D;N
PrimateAI	Benign	0.45	T
Vest4		0.068, 0.056, 0.042
MVP		0.47
ClinPred		0.019	T
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

Other links and lift over

dbSNP: rs149495971; hg19: chrX-110574222;