6-24290975-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_016356.5(DCDC2):c.661A>G(p.Ser221Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,613,216 control chromosomes in the GnomAD database, including 344,434 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S221N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.52 ( 25455 hom., cov: 32)

Exomes 𝑓: 0.65 ( 318979 hom. )

Consequence

DCDC2
NM_016356.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.35

Publications

53 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 6-24290975-T-C is Benign according to our data. Variant chr6-24290975-T-C is described in ClinVar as Benign. ClinVar VariationId is 516888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCDC2	NM_016356.5 link	c.661A>G	p.Ser221Gly	missense_variant	Exon 5 of 10	ENST00000378454.8	NP_057440.2
DCDC2	NM_001195610.2 link	c.661A>G	p.Ser221Gly	missense_variant	Exon 6 of 11		NP_001182539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCDC2	ENST00000378454.8 link	c.661A>G	p.Ser221Gly	missense_variant	Exon 5 of 10	1	NM_016356.5	ENSP00000367715.3

Frequencies

GnomAD3 genomes

AF:

0.525

AC:

79752

AN:

151970

Hom.:

25451

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.669

Gnomad AMR

AF:

0.638

Gnomad ASJ

AF:

0.692

Gnomad EAS

AF:

0.791

Gnomad SAS

AF:

0.660

Gnomad FIN

AF:

0.746

Gnomad MID

AF:

0.560

Gnomad NFE

AF:

0.658

Gnomad OTH

AF:

0.539

GnomAD2 exomes

AF:

0.654

AC:

164087

AN:

251070

AF XY:

0.660

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.745

Gnomad ASJ exome

AF:

0.679

Gnomad EAS exome

AF:

0.801

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.656

Gnomad OTH exome

AF:

0.656

GnomAD4 exome

AF:

0.654

AC:

955781

AN:

1461128

Hom.:

318979

Cov.:

AF XY:

0.656

AC XY:

476950

AN XY:

726906

show subpopulations

African (AFR)

AF:

0.117

AC:

3916

AN:

33470

American (AMR)

AF:

0.732

AC:

32696

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.676

AC:

17650

AN:

26124

East Asian (EAS)

AF:

0.785

AC:

31146

AN:

39662

South Asian (SAS)

AF:

0.661

AC:

57005

AN:

86178

European-Finnish (FIN)

AF:

0.743

AC:

39657

AN:

53386

Middle Eastern (MID)

AF:

0.592

AC:

3411

AN:

5762

European-Non Finnish (NFE)

AF:

0.659

AC:

732166

AN:

1111492

Other (OTH)

AF:

0.632

AC:

38134

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

15536

31073

46609

62146

77682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19006

38012

57018

76024

95030

<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:

0.524

AC:

79758

AN:

152088

Hom.:

25455

Cov.:

AF XY:

0.535

AC XY:

39747

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.140

AC:

5806

AN:

41496

American (AMR)

AF:

0.638

AC:

9754

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.692

AC:

2400

AN:

3470

East Asian (EAS)

AF:

0.792

AC:

4095

AN:

5172

South Asian (SAS)

AF:

0.658

AC:

3175

AN:

4822

European-Finnish (FIN)

AF:

0.746

AC:

7887

AN:

10572

Middle Eastern (MID)

AF:

0.541

AC:

159

AN:

294

European-Non Finnish (NFE)

AF:

0.658

AC:

44732

AN:

67962

Other (OTH)

AF:

0.541

AC:

1141

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1497

2995

4492

5990

7487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<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:

0.617

Hom.:

148623

Bravo

AF:

0.496

TwinsUK

AF:

0.662

AC:

2454

ALSPAC

AF:

0.664

AC:

2559

ESP6500AA

AF:

0.154

AC:

678

ESP6500EA

AF:

0.651

AC:

5597

ExAC

AF:

0.639

AC:

77563

Asia WGS

AF:

0.682

AC:

2375

AN:

3478

EpiCase

AF:

0.645

EpiControl

AF:

0.651

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 13, 2017

GeneDx

Significance: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.

Isolated neonatal sclerosing cholangitis

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive nonsyndromic hearing loss 66

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nephronophthisis 19

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.035

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.65

PhyloP100

1.3

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.19

REVEL

Benign

0.23

Sift

Benign

0.22

Sift4G

Benign

0.31

Vest4

0.031

ClinPred

0.0045

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.22

Mutation Taster

=69/31

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.64

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.64

Position offset: 0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over