rs386833753

Variant names:

• chr4-15569290-C-A
• rs386833753
• NM_001378615.1:c.3399-3C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001378615.1(CC2D2A):​c.3399-3C>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000641 in 1,404,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 splice_region, intron
• Scores: Splicing: ADA: 0.9982
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.70
• 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

LOC124900671 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-15569290-C-A is Pathogenic according to our data. Variant chr4-15569290-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56305.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3399-3C>A		splice_region intron	N/A	NP_001365544.1
	CC2D2A	NM_001080522.2		c.3399-3C>A		splice_region intron	N/A	NP_001073991.2
	CC2D2A	NM_001378617.1		c.3252-3C>A		splice_region intron	N/A	NP_001365546.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.3399-3C>A		splice_region intron	N/A	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.3399-3C>A		splice_region intron	N/A	ENSP00000421809.1
	CC2D2A	ENST00000634028.2	TSL:1	n.3252-3C>A		splice_region intron	N/A	ENSP00000488669.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000641 AC: 9 AN: 1404270 Hom.: 0 Cov.: 27 AF XY: 0.00000720 AC XY: 5 AN XY: 694758

African (AFR) AF: 0.00 AC: 0 AN: 32408

American (AMR) AF: 0.00 AC: 0 AN: 38448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25282

East Asian (EAS) AF: 0.00 AC: 0 AN: 37930

South Asian (SAS) AF: 0.00 AC: 0 AN: 80180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00000651 AC: 7 AN: 1075116

Other (OTH) AF: 0.0000343 AC: 2 AN: 58358

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Joubert syndrome Pathogenic:1

Sep 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with Meckel-Gruber syndrome (PMID: 19777577). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 27 of the CC2D2A gene. It does not directly change the encoded amino acid sequence of the CC2D2A protein. It affects a nucleotide within the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 56305). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.

Meckel syndrome, type 6 Pathogenic:1

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.77
PhyloP100		3.7
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.90		Position offset: 3

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

Other links and lift over

dbSNP: rs386833753; hg19: chr4-15570913;