rs757704417

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 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:6

Conservation

PhyloP100: 3.16

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 id is 180688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24357626-GAC-G is described in Lovd as [Pathogenic].

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	UniProt
DCDC2	ENST00000378454.8 link	c.123_124delGT	p.Ser42GlnfsTer72	frameshift_variant	Exon 1 of 10	1	NM_016356.5	ENSP00000367715.3	Q9UHG0-1
KAAG1	ENST00000274766.2 link	n.727_728delAC		non_coding_transcript_exon_variant	Exon 1 of 1	6	NM_181337.4
DCDC2	ENST00000436313.1 link	c.24_25delGT	p.Ser9SerfsTer80	frameshift_variant	Exon 1 of 3	3		ENSP00000410939.1	H0Y784

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

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248076

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134636

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Isolated neonatal sclerosing cholangitis

Pathogenic:2

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 -

Jan 08, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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%). -

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over