rs386833760

Variant names:

• chr4-15587928-AG-A
• rs386833760
• ENST00000424120.6:c.4168delG

Your query was ambiguous. Multiple possible variants found:

• chr4-15587928-AG-A
• chr4-15587928-AG-AGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_001080522.2(CC2D2A):​c.4179+1delG variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000767 in 1,578,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: CC2D2A NM_001080522.2 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 8.11
• Publications: 4 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023442319 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.1, offset of -1, new splice context is: tgaGTaaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 4-15587928-AG-A is Pathogenic according to our data. Variant chr4-15587928-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 56312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080522.2. 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.4179+1delG		splice_donor intron	N/A	NP_001365544.1
	CC2D2A	NM_001080522.2		c.4179+1delG		splice_donor intron	N/A	NP_001073991.2
	CC2D2A	NM_001378617.1		c.4032+1delG		splice_donor intron	N/A	NP_001365546.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.4168delG	p.Ala1390ValfsTer7	frameshift	Exon 32 of 37	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.4168delG	p.Ala1390ValfsTer7	frameshift	Exon 33 of 38	ENSP00000421809.1
	CC2D2A	ENST00000634028.2	TSL:1	n.4021delG		non_coding_transcript_exon	Exon 29 of 34	ENSP00000488669.2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152138 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000931 AC: 23 AN: 247170 AF XY: 0.0000969

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000294

Gnomad ASJ exome AF: 0.000902

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.0000652 AC: 93 AN: 1425792 Hom.: 0 Cov.: 24 AF XY: 0.0000661 AC XY: 47 AN XY: 711328

African (AFR) AF: 0.00 AC: 0 AN: 32664

American (AMR) AF: 0.000180 AC: 8 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.000929 AC: 24 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.00 AC: 0 AN: 85102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000528 AC: 57 AN: 1080184

Other (OTH) AF: 0.0000677 AC: 4 AN: 59098

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152256 Hom.: 0 Cov.: 31 AF XY: 0.000295 AC XY: 22 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.00118 AC: 18 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000283

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Meckel syndrome, type 6 (3)
2	-	-	Joubert syndrome 9 (2)
2	-	-	not provided (2)
1	-	-	Anencephaly;C0152427:Polydactyly;C3887499:Renal cyst (1)
1	-	-	Clubfoot;C0022680:Polycystic kidney disease;C0079924:Oligohydramnios;C0426790:Narrow chest;C4282400:Polydactyly, postaxial, type A1;C4551563:Microcephaly;C4551722:Encephalocele (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5436837:COACH syndrome 2;C5676970:Retinitis pigmentosa 93 (1)
1	-	-	Meckel-Gruber syndrome (1)
1	-	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
1	-	-	Retinitis pigmentosa 93 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.83		Position offset: 1

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

Other links and lift over

dbSNP: rs386833760; hg19: chr4-15589551;