NM_016356.5:c.123_124delGT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_016356.5(DCDC2):c.123_124delGT(p.Ser42GlnfsTer72) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

DCDC2
NM_016356.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.16

Publications

3 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 links:

KAAG1 (HGNC:21031): (kidney associated DCDC2 antisense RNA 1)

KAAG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-24357626-GAC-G is Pathogenic according to our data. Variant chr6-24357626-GAC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 180688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DCDC2	NM_016356.5 link	c.123_124delGT	p.Ser42GlnfsTer72	frameshift_variant	Exon 1 of 10	ENST00000378454.8	NP_057440.2
DCDC2	NM_001195610.2 link	c.123_124delGT	p.Ser42GlnfsTer72	frameshift_variant	Exon 2 of 11		NP_001182539.1
KAAG1	NR_174942.1 link	n.727_728delAC		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DCDC2	ENST00000378454.8 link	c.123_124delGT	p.Ser42GlnfsTer72	frameshift_variant	Exon 1 of 10	1	NM_016356.5	ENSP00000367715.3
DCDC2	ENST00000436313.1 link	c.24_25delGT	p.Ser9SerfsTer80	frameshift_variant	Exon 1 of 3	3		ENSP00000410939.1
KAAG1	ENST00000274766.2 link	n.727_728delAC		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

248076

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461154

Hom.:

AF XY:

0.0000179

AC XY:

AN XY:

726892

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1112010

Other (OTH)

AF:

0.0000331

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Isolated neonatal sclerosing cholangitis

Pathogenic:2

Jan 08, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Mar 14, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence variant is a 2 nucleotide deletion (delGT) in the exon 1 of 10 of the DCDC2 gene that results in an early termination codon 72 amino acids downstream of the frameshift at codon 42. This variant is predicted to generate a non-functional allele through either the expression of a truncated protein or a loss of doublecortin domain containing 2 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 180688) that has been observed in both homozygous and compound heterozygous states in individuals affected by hepatic ciliopathy and neonatal sclerosing cholangitis (PMID: 25557784, 37296768, 27469900, 36938759). This variant is present in 5 of 400306 alleles (0.0012%) in the gnomAD population dataset. Functional studies have found that the protein resulting from this variant failed to properly localize in the primary cilium, did not interact with its protein partners, and could not rescue mouse kidney cells in which DCDC2 expression was knocked-down (PMID: 25557784). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PS3, PVS1

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

Pathogenic:1

Apr 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ser42Glnfs*72) in the DCDC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCDC2 are known to be pathogenic (PMID: 27319779, 27469900). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180688). This premature translational stop signal has been observed in individual(s) with DCDC2-related conditions (PMID: 25557784, 27469900). This variant is present in population databases (rs757704417, gnomAD 0.003%).

not provided

Pathogenic:1

Sep 07, 2023

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the DCDC2 gene demonstrated a 2 base pair deletion in exon 1, c.123_124del. This sequence change results in an amino acid frameshift and creates a premature stop codon 72 amino acids downstream of the change, p.Ser42Glnfs*72. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated DCDC2 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.004% in the European (non-Finnish) subpopulation (dbSNP rs757704417). This pathogenic sequence change has previously been described in an individual with DCDC2-related disorders [PMID: 25557784]; in addition, other deletions/duplications in the DCDC2 gene have been described in several individuals with DCDC2-related disorders [PMID: 31821705, 25557784]. Functional studies in cell models of the p.Ser42Glnfs*72 sequence change demonstrate altered subcellular localization of the altered DCDC2 protein versus wild-type DCDC2 [PMID: 25557784]. These collective evidences indicate that this sequence change is pathogenic.

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

Pathogenic:1

Apr 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nephronophthisis 19

Pathogenic:1

Jan 08, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Dyslexia, susceptibility to, 2

Pathogenic:1

Sep 20, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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