6-24357457-CTTGAGTTTCTTGAAGGCTTCCTGGCCTCCAGCCACGTAATTGCCCCCGCTCTGGATCTGGTCTAGCTTCCG-C

Position:

• chr6-24357457-CTTGAGTTTCTTGAAGGCTTCCTGGCCTCCAGCCACGTAATTGCCCCCGCTCTGGATCTGGTCTAGCTTCCG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_016356.5(DCDC2):​c.223_293delCGGAAGCTAGACCAGATCCAGAGCGGGGGCAATTACGTGGCTGGAGGCCAGGAAGCCTTCAAGAAACTCAA​(p.Arg75fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCDC2 NM_016356.5 frameshift, splice_region
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.18

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]

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

KAAG1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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 6-24357457-CTTGAGTTTCTTGAAGGCTTCCTGGCCTCCAGCCACGTAATTGCCCCCGCTCTGGATCTGGTCTAGCTTCCG-C is Pathogenic according to our data. Variant chr6-24357457-CTTGAGTTTCTTGAAGGCTTCCTGGCCTCCAGCCACGTAATTGCCCCCGCTCTGGATCTGGTCTAGCTTCCG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 917935.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCDC2	NM_016356.5	c.223_293delCGGAAGCTAGACCAGATCCAGAGCGGGGGCAATTACGTGGCTGGAGGCCAGGAAGCCTTCAAGAAACTCAA	p.Arg75fs	frameshift_variant, splice_region_variant	1/10	ENST00000378454.8	NP_057440.2
DCDC2	NM_001195610.2	c.223_293delCGGAAGCTAGACCAGATCCAGAGCGGGGGCAATTACGTGGCTGGAGGCCAGGAAGCCTTCAAGAAACTCAA	p.Arg75fs	frameshift_variant, splice_region_variant	2/11		NP_001182539.1
KAAG1	NR_174942.1	n.556_626delTTGAGTTTCTTGAAGGCTTCCTGGCCTCCAGCCACGTAATTGCCCCCGCTCTGGATCTGGTCTAGCTTCCG		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCDC2	ENST00000378454.8	c.223_293delCGGAAGCTAGACCAGATCCAGAGCGGGGGCAATTACGTGGCTGGAGGCCAGGAAGCCTTCAAGAAACTCAA	p.Arg75fs	frameshift_variant, splice_region_variant	1/10	1	NM_016356.5	ENSP00000367715.3
KAAG1	ENST00000274766.2	n.556_626delTTGAGTTTCTTGAAGGCTTCCTGGCCTCCAGCCACGTAATTGCCCCCGCTCTGGATCTGGTCTAGCTTCCG		non_coding_transcript_exon_variant	1/1	6	NM_181337.4
DCDC2	ENST00000436313.1	c.124_194delCGGAAGCTAGACCAGATCCAGAGCGGGGGCAATTACGTGGCTGGAGGCCAGGAAGCCTTCAAGAAACTCAA	p.Arg42fs	frameshift_variant, splice_region_variant	1/3	3		ENSP00000410939.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nephronophthisis 19 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1760494153; hg19: chr6-24357685;