X-111312507-C-G

Position:

• chrX-111312507-C-G

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.1044+132G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 583,640 control chromosomes in the GnomAD database, including 38 homozygotes. There are 706 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (30 hom., 457 hem., cov: 23)
  • Exomes 𝑓: 0.0020 (8 hom. 249 hem.)
• Consequence: DCX NM_001195553.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.235

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 (BayesDel_noAF=-0.85).
• BP6: Variant X-111312507-C-G is Benign according to our data. Variant chrX-111312507-C-G is described in ClinVar as [Benign]. Clinvar id is 1179444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (1610/112434) while in subpopulation AFR AF= 0.0494 (1528/30946). AF 95% confidence interval is 0.0473. There are 30 homozygotes in gnomad4. There are 457 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCX	NM_001195553.2	c.1044+132G>C		intron_variant		ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.1044+132G>C		intron_variant		2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.1044+132G>C		intron_variant		5		ENSP00000348553.4
DCX	ENST00000637453.1	c.1044+132G>C		intron_variant		5		ENSP00000490357.1
DCX	ENST00000637570.1	c.1029+132G>C		intron_variant		5		ENSP00000490878.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 1612 AN: 112381 Hom.: 30 Cov.: 23 AF XY: 0.0133 AC XY: 459 AN XY: 34543

Gnomad AFR AF: 0.0495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00527

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.00727

GnomAD4 exome AF: 0.00203 AC: 957 AN: 471206 Hom.: 8 AF XY: 0.00176 AC XY: 249 AN XY: 141860

Gnomad4 AFR exome AF: 0.0509

Gnomad4 AMR exome AF: 0.00422

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000288

Gnomad4 OTH exome AF: 0.00413

GnomAD4 genome AF: 0.0143 AC: 1610 AN: 112434 Hom.: 30 Cov.: 23 AF XY: 0.0132 AC XY: 457 AN XY: 34606

Gnomad4 AFR AF: 0.0494

Gnomad4 AMR AF: 0.00526

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000244

Gnomad4 OTH AF: 0.00718

Alfa AF: 0.0107 Hom.: 31

Bravo AF: 0.0163

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.42

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: rs10482456; hg19: chrX-110555735;