4-15511381-GGAA-GGAAGAA

Variant names:

• chr4-15511381-G-GGAA
• rs386833764
• NM_001378615.1:c.685_687dupGAA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_001378615.1(CC2D2A):​c.685_687dupGAA​(p.Glu229dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00000214 in 1,402,384 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24
• Publications: 10 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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

LOC124900672 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001378615.1

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.685_687dupGAA	p.Glu229dup	conservative_inframe_insertion	Exon 8 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.685_687dupGAA	p.Glu229dup	conservative_inframe_insertion	Exon 9 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.538_540dupGAA	p.Glu180dup	conservative_inframe_insertion	Exon 6 of 35	NP_001365546.1	H0Y941

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.685_687dupGAA	p.Glu229dup	conservative_inframe_insertion	Exon 8 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.685_687dupGAA	p.Glu229dup	conservative_inframe_insertion	Exon 9 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000513811.5	TSL:1	n.865_867dupGAA		non_coding_transcript_exon	Exon 8 of 18

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1402384 Hom.: 0 Cov.: 29 AF XY: 0.00000144 AC XY: 1 AN XY: 695940

African (AFR) AF: 0.00 AC: 0 AN: 29138

American (AMR) AF: 0.00 AC: 0 AN: 31064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24444

East Asian (EAS) AF: 0.00 AC: 0 AN: 35808

South Asian (SAS) AF: 0.00 AC: 0 AN: 74986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1090402

Other (OTH) AF: 0.00 AC: 0 AN: 57992

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 64

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2

Splicing

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

Other links and lift over

dbSNP: rs386833764; hg19: chr4-15513004;