X-111312782-A-G

Variant names:

• chrX-111312782-A-G
• rs113181679
• NM_001195553.2:c.947-46T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195553.2(DCX):​c.947-46T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 1,133,172 control chromosomes in the GnomAD database, including 240 homozygotes. There are 6,864 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 0.013 (20 hom., 389 hem., cov: 23)
  • Exomes 𝑓: 0.021 (220 hom. 6475 hem.)
• Consequence: DCX NM_001195553.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.07

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-111312782-A-G is Benign according to our data. Variant chrX-111312782-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 262927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (1489/111976) while in subpopulation NFE AF = 0.0211 (1122/53187). AF 95% confidence interval is 0.0201. There are 20 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCX	NM_001195553.2	c.947-46T>C		intron_variant	Intron 5 of 6	ENST00000636035.2	NP_001182482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCX	ENST00000636035.2	c.947-46T>C		intron_variant	Intron 5 of 6	2	NM_001195553.2	ENSP00000490614.1
DCX	ENST00000356220.8	c.947-46T>C		intron_variant	Intron 6 of 7	5		ENSP00000348553.4
DCX	ENST00000637453.1	c.947-46T>C		intron_variant	Intron 5 of 6	5		ENSP00000490357.1
DCX	ENST00000637570.1	c.932-46T>C		intron_variant	Intron 5 of 6	5		ENSP00000490878.1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 1488 AN: 111924 Hom.: 20 Cov.: 23

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.0147

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00677

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0133

GnomAD2 exomes AF: 0.0137 AC: 2393 AN: 174853 AF XY: 0.0134

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0213 AC: 21758 AN: 1021196 Hom.: 220 Cov.: 22 AF XY: 0.0217 AC XY: 6475 AN XY: 298512

Gnomad4 AFR exome AF: 0.00269 AC: 67 AN: 24927

Gnomad4 AMR exome AF: 0.00563 AC: 196 AN: 34796

Gnomad4 ASJ exome AF: 0.0188 AC: 355 AN: 18882

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 29856

Gnomad4 SAS exome AF: 0.00730 AC: 378 AN: 51804

Gnomad4 FIN exome AF: 0.0139 AC: 562 AN: 40289

Gnomad4 NFE exome AF: 0.0250 AC: 19333 AN: 773146

Gnomad4 Remaining exome AF: 0.0187 AC: 816 AN: 43607

GnomAD4 genome AF: 0.0133 AC: 1489 AN: 111976 Hom.: 20 Cov.: 23 AF XY: 0.0114 AC XY: 389 AN XY: 34150

Gnomad4 AFR AF: 0.00315 AC: 0.00314843 AN: 0.00314843

Gnomad4 AMR AF: 0.00974 AC: 0.00973811 AN: 0.00973811

Gnomad4 ASJ AF: 0.0162 AC: 0.0162325 AN: 0.0162325

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00679 AC: 0.00678733 AN: 0.00678733

Gnomad4 FIN AF: 0.0124 AC: 0.0123839 AN: 0.0123839

Gnomad4 NFE AF: 0.0211 AC: 0.0210954 AN: 0.0210954

Gnomad4 OTH AF: 0.0131 AC: 0.0131234 AN: 0.0131234

Alfa AF: 0.0169 Hom.: 141

Bravo AF: 0.0128

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 10, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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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	-0.55
CADD	Benign	18
DANN	Benign	0.74
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs113181679; hg19: chrX-110556010;