X-111301414-G-T

Variant names:

• chrX-111301414-G-T
• rs111957035
• NM_001195553.2:c.*273C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001195553.2(DCX):​c.*273C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 290,634 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000069 (0 hom. 0 hem.)
• Consequence: DCX NM_001195553.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.237
• Publications: 0 publications found

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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• subcortical band heterotopia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195553.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCX	NM_001195553.2	MANE Select	c.*273C>A		3_prime_UTR	Exon 7 of 7	NP_001182482.1	A8K340
	DCX	NM_000555.3		c.*273C>A		3_prime_UTR	Exon 7 of 7	NP_000546.2	O43602
	DCX	NM_001369370.1		c.*273C>A		3_prime_UTR	Exon 7 of 7	NP_001356299.1	A8K340

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCX	ENST00000636035.2	TSL:2 MANE Select	c.*273C>A		3_prime_UTR	Exon 7 of 7	ENSP00000490614.1	A8K340
	DCX	ENST00000358070.10	TSL:1	c.*273C>A		3_prime_UTR	Exon 7 of 7	ENSP00000350776.6	A0A9S7JGE9
	DCX	ENST00000356220.8	TSL:5	c.*273C>A		3_prime_UTR	Exon 8 of 8	ENSP00000348553.4	A8K340

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000688 AC: 2 AN: 290634 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 89760

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 8862

American (AMR) AF: 0.00 AC: 0 AN: 13380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8722

East Asian (EAS) AF: 0.00 AC: 0 AN: 20046

South Asian (SAS) AF: 0.00 AC: 0 AN: 24627

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1248

European-Non Finnish (NFE) AF: 0.00000569 AC: 1 AN: 175774

Other (OTH) AF: 0.0000572 AC: 1 AN: 17495

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 3

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.53
PhyloP100		0.24

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

Other links and lift over

dbSNP: rs111957035; hg19: chrX-110544642;