Genetic Variant DCDC2:p.Asp348Asp (chr6-24178612-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_016356.5(DCDC2):c.1044C>T(p.Asp348Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,612,918 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 29 hom. )

Consequence

DCDC2
NM_016356.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.237

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

DCDC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 6-24178612-G-A is Benign according to our data. Variant chr6-24178612-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.237 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0029 (441/152016) while in subpopulation AMR AF = 0.00399 (61/15270). AF 95% confidence interval is 0.00319. There are 4 homozygotes in GnomAd4. There are 220 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016356.5. 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
	DCDC2	NM_016356.5	MANE Select	c.1044C>T	p.Asp348Asp	synonymous	Exon 9 of 10	NP_057440.2	Q9UHG0-1
	DCDC2	NM_001195610.2		c.1044C>T	p.Asp348Asp	synonymous	Exon 10 of 11	NP_001182539.1	Q9UHG0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DCDC2	ENST00000378454.8	TSL:1 MANE Select	c.1044C>T	p.Asp348Asp	synonymous	Exon 9 of 10	ENSP00000367715.3	Q9UHG0-1
DCDC2	ENST00000378450.6	TSL:1	c.303C>T	p.Asp101Asp	synonymous	Exon 2 of 3	ENSP00000367711.3	Q9UHG0-2
DCDC2	ENST00000883243.1		c.1044C>T	p.Asp348Asp	synonymous	Exon 10 of 11	ENSP00000553302.1

Frequencies

GnomAD3 genomes

AF:

0.00290

AC:

441

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.0303

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00391

AC:

980

AN:

250470

AF XY:

0.00414

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.00109

Gnomad FIN exome

AF:

0.000377

Gnomad NFE exome

AF:

0.00382

Gnomad OTH exome

AF:

0.00393

GnomAD4 exome

AF:

0.00315

AC:

4603

AN:

1460902

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

2390

AN XY:

726752

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33456

American (AMR)

AF:

0.00253

AC:

113

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

743

AN:

26066

East Asian (EAS)

AF:

0.000529

AC:

AN:

39700

South Asian (SAS)

AF:

0.00407

AC:

351

AN:

86200

European-Finnish (FIN)

AF:

0.000170

AC:

AN:

52880

Middle Eastern (MID)

AF:

0.00902

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00273

AC:

3036

AN:

1111754

Other (OTH)

AF:

0.00444

AC:

268

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

233

466

700

933

1166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00290

AC:

441

AN:

152016

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

220

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.000724

AC:

AN:

41452

American (AMR)

AF:

0.00399

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0303

AC:

105

AN:

3470

East Asian (EAS)

AF:

0.000968

AC:

AN:

5166

South Asian (SAS)

AF:

0.00311

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

10538

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00316

AC:

215

AN:

67986

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

112

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:

0.00514

Hom.:

Bravo

AF:

0.00319

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00557

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Autosomal recessive nonsyndromic hearing loss 66;C4015542:Nephronophthisis 19;C4479344:Isolated neonatal sclerosing cholangitis (1)

Autosomal recessive nonsyndromic hearing loss 66;C4479344:Isolated neonatal sclerosing cholangitis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.9

(source)

DANN

Benign

0.39

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