Genetic Variant NM_001195553.2:c.*273C>T (chrX-111301414-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001195553.2(DCX):c.*273C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 402,534 control chromosomes in the GnomAD database, including 2 homozygotes. There are 181 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 0.0047 ( 2 hom., 142 hem., cov: 23)

Exomes 𝑓: 0.00071 ( 0 hom. 39 hem. )

Consequence

DCX
NM_001195553.2 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.237

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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant X-111301414-G-A is Benign according to our data. Variant chrX-111301414-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1212152.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00475 (531/111900) while in subpopulation AFR AF = 0.0161 (497/30799). AF 95% confidence interval is 0.015. There are 2 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 XL,AR gene

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.00472

AC:

528

AN:

111845

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00237

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00465

GnomAD4 exome

AF:

0.000709

AC:

206

AN:

290634

Hom.:

Cov.:

AF XY:

0.000434

AC XY:

AN XY:

89760

show subpopulations

African (AFR)

AF:

0.0175

AC:

155

AN:

8862

American (AMR)

AF:

0.00120

AC:

AN:

13380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8722

East Asian (EAS)

AF:

0.00

AC:

AN:

20046

South Asian (SAS)

AF:

0.00

AC:

AN:

24627

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20480

Middle Eastern (MID)

AF:

0.000801

AC:

AN:

1248

European-Non Finnish (NFE)

AF:

0.0000455

AC:

AN:

175774

Other (OTH)

AF:

0.00149

AC:

AN:

17495

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00475

AC:

531

AN:

111900

Hom.:

Cov.:

AF XY:

0.00417

AC XY:

142

AN XY:

34076

show subpopulations

African (AFR)

AF:

0.0161

AC:

497

AN:

30799

American (AMR)

AF:

0.00237

AC:

AN:

10542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3582

South Asian (SAS)

AF:

0.00

AC:

AN:

2648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53172

Other (OTH)

AF:

0.00459

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00107

Hom.:

Bravo

AF:

0.00621

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.2

(source)

DANN

Benign

0.52

PhyloP100

0.24

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over