rs386833761

chr4-15587928-A-AGchr4-15587928-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP3

The NM_001378615.1(CC2D2A):c.4179+1dup variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CC2D2A NM_001378615.1 frameshift, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.11

Genes affected

CC2D2A (HGNC:29253): (coiled-coil and C2 domain containing 2A) This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1	c.4179+1dup		frameshift_variant, splice_region_variant	32/37	ENST00000424120.6
CC2D2A	NM_001080522.2	c.4179+1dup		frameshift_variant, splice_region_variant	33/38
CC2D2A	NM_001378617.1	c.4032+1dup		frameshift_variant, splice_region_variant	30/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6	c.4179+1dup		frameshift_variant, splice_region_variant	32/37	5	NM_001378615.1	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.63		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs386833760; hg19: chr4-15589551;