4-15597467-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001080522.2(CC2D2A):c.4496+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000643 in 1,399,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

CC2D2A
NM_001080522.2 splice_donor, intron

Scores

Splicing: ADA: 0.9912

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.67

Publications

1 publications found

Variant links:

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

CC2D2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-15597467-T-C is Pathogenic according to our data. Variant chr4-15597467-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 631940.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CC2D2A	NM_001378615.1	MANE Select	c.4496+2T>C	splice_donor intron	N/A	NP_001365544.1
CC2D2A	NM_001080522.2		c.4496+2T>C	splice_donor intron	N/A	NP_001073991.2
CC2D2A	NM_001378617.1		c.4349+2T>C	splice_donor intron	N/A	NP_001365546.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.4496+2T>C	splice_donor intron	N/A	ENSP00000403465.1
CC2D2A	ENST00000503292.6	TSL:1	c.4496+2T>C	splice_donor intron	N/A	ENSP00000421809.1
CC2D2A	ENST00000634028.2	TSL:1	n.*54+2T>C	splice_donor intron	N/A	ENSP00000488669.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000124

AC:

AN:

161224

AF XY:

0.0000235

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000643

AC:

AN:

1399346

Hom.:

Cov.:

AF XY:

0.00000869

AC XY:

AN XY:

690452

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31664

American (AMR)

AF:

0.00

AC:

AN:

35904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25214

East Asian (EAS)

AF:

0.00

AC:

AN:

36022

South Asian (SAS)

AF:

0.0000883

AC:

AN:

79300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1078120

Other (OTH)

AF:

0.00

AC:

AN:

58036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.000630

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000192

AC:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.95

PhyloP100

4.7

GERP RS

5.5

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.62

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over