rs760040426

chr6-24302046-T-Cchr6-24302046-T-G

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_016356.5(DCDC2):c.349-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000234 in 1,452,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: DCDC2 NM_016356.5 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.23

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]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 11, offset of -1, new splice context is: ttttttcctttgcttttaAGggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 6-24302046-T-C is Pathogenic according to our data. Variant chr6-24302046-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 180689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24302046-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCDC2	NM_016356.5	c.349-2A>G		splice_acceptor_variant		ENST00000378454.8
DCDC2	NM_001195610.2	c.349-2A>G		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCDC2	ENST00000378454.8	c.349-2A>G		splice_acceptor_variant		1	NM_016356.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000252 AC: 6 AN: 238132 Hom.: 0 AF XY: 0.0000232 AC XY: 3 AN XY: 129248

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: 0.0000453

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1452274 Hom.: 0 Cov.: 33 AF XY: 0.0000235 AC XY: 17 AN XY: 722500

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: 0.0000298

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 19 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 08, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 27, 2022	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 17, 2023

This variant is present in population databases (rs760040426, gnomAD 0.005%). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 3 (also known as exon 4 in literature) and introduces a premature termination codon (PMID: 25557784). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 180689). Disruption of this splice site has been observed in individual(s) with nephronophthisis-related ciliopathy (PMID: 25557784). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change affects an acceptor splice site in intron 2 of the DCDC2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 04, 2018

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	35
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D
GERP RS		6.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -1
DS_AL_spliceai		1.0		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs760040426; hg19: chr6-24302274;