Genetic Variant DCDC2:c.923-1286T>A (chr6-24206388-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_016356.5(DCDC2):c.923-1286T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 152,046 control chromosomes in the GnomAD database, including 30,329 homozygotes. 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: 𝑓 0.59 ( 30329 hom., cov: 32)

Consequence

DCDC2
NM_016356.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.945

Publications

2 publications found

Variant links:

Genes affected

DCDC2 (HGNC:18141): (doublecortin domain containing 2) This gene encodes a doublecortin domain-containing family member. The doublecortin domain has been demonstrated to bind tubulin and enhance microtubule polymerization. This family member is thought to function in neuronal migration where it may affect the signaling of primary cilia. Mutations in this gene have been associated with reading disability (RD) type 2, also referred to as developmental dyslexia. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jan 2013]

DCDC2 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
isolated neonatal sclerosing cholangitis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
nephronophthisis 19
Inheritance: AR Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Boichis syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 66
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

DCDC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCDC2	NM_016356.5 link	c.923-1286T>A		intron_variant	Intron 7 of 9	ENST00000378454.8	NP_057440.2
DCDC2	NM_001195610.2 link	c.923-1286T>A		intron_variant	Intron 8 of 10		NP_001182539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCDC2	ENST00000378454.8 link	c.923-1286T>A		intron_variant	Intron 7 of 9	1	NM_016356.5	ENSP00000367715.3		Q9UHG0-1

Frequencies

GnomAD3 genomes

AF:

0.595

AC:

90331

AN:

151928

Hom.:

30325

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.692

Gnomad AMR

AF:

0.682

Gnomad ASJ

AF:

0.687

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.652

Gnomad FIN

AF:

0.824

Gnomad MID

AF:

0.650

Gnomad NFE

AF:

0.731

Gnomad OTH

AF:

0.612

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.594

AC:

90349

AN:

152046

Hom.:

30329

Cov.:

AF XY:

0.600

AC XY:

44620

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.263

AC:

10912

AN:

41468

American (AMR)

AF:

0.682

AC:

10420

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.687

AC:

2383

AN:

3470

East Asian (EAS)

AF:

0.577

AC:

2990

AN:

5178

South Asian (SAS)

AF:

0.652

AC:

3137

AN:

4814

European-Finnish (FIN)

AF:

0.824

AC:

8719

AN:

10576

Middle Eastern (MID)

AF:

0.627

AC:

183

AN:

292

European-Non Finnish (NFE)

AF:

0.731

AC:

49682

AN:

67956

Other (OTH)

AF:

0.613

AC:

1296

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1548

3096

4644

6192

7740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.636

Hom.:

3994

Bravo

AF:

0.564

Asia WGS

AF:

0.590

AC:

2054

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.26

(source)

DANN

Benign

0.67

PhyloP100

-0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over