rs863225177

Variant names:

• chr4-15533227-AAAG-A
• rs863225177
• NM_001378615.1:c.1503_1505delAGA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_001378615.1(CC2D2A):​c.1503_1505delAGA​(p.Lys501_Asp502delinsAsn) variant causes a disruptive inframe deletion 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CC2D2A NM_001378615.1 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.93
• Publications: 1 publications found

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]

CC2D2A Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• retinitis pigmentosa 93

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001378615.1. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 4-15533227-AAAG-A is Pathogenic according to our data. Variant chr4-15533227-AAAG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217613.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378615.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.1503_1505delAGA	p.Lys501_Asp502delinsAsn	disruptive_inframe_deletion	Exon 14 of 37	NP_001365544.1
	CC2D2A	NM_001080522.2		c.1503_1505delAGA	p.Lys501_Asp502delinsAsn	disruptive_inframe_deletion	Exon 15 of 38	NP_001073991.2
	CC2D2A	NM_001378617.1		c.1356_1358delAGA	p.Lys452_Asp453delinsAsn	disruptive_inframe_deletion	Exon 12 of 35	NP_001365546.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.1503_1505delAGA	p.Lys501_Asp502delinsAsn	disruptive_inframe_deletion	Exon 14 of 37	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.1503_1505delAGA	p.Lys501_Asp502delinsAsn	disruptive_inframe_deletion	Exon 15 of 38	ENSP00000421809.1
	CC2D2A	ENST00000513811.5	TSL:1	n.1683_1685delAGA		non_coding_transcript_exon	Exon 14 of 18

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Joubert syndrome 9 (1)
-	1	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863225177; hg19: chr4-15534850;