4-15601414-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001378615.1(CC2D2A):c.4852C>T(p.Arg1618Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000567 in 1,482,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1618G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.38

Publications

4 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: 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

CC2D2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37853584).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CC2D2A	NM_001378615.1	MANE Select	c.4852C>T	p.Arg1618Cys	missense	Exon 37 of 37	NP_001365544.1	Q9P2K1-4
CC2D2A	NM_001080522.2		c.4852C>T	p.Arg1618Cys	missense	Exon 38 of 38	NP_001073991.2	Q9P2K1-4
CC2D2A	NM_001378617.1		c.4705C>T	p.Arg1569Cys	missense	Exon 35 of 35	NP_001365546.1	H0Y941

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.4852C>T	p.Arg1618Cys	missense	Exon 37 of 37	ENSP00000403465.1	Q9P2K1-4
CC2D2A	ENST00000503292.6	TSL:1	c.4852C>T	p.Arg1618Cys	missense	Exon 38 of 38	ENSP00000421809.1	Q9P2K1-4
CC2D2A	ENST00000634028.2	TSL:1	n.*410C>T		non_coding_transcript_exon	Exon 34 of 34	ENSP00000488669.2	A0A0J9YY35

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000694

AC:

AN:

158472

AF XY:

0.0000815

show subpopulations

Gnomad AFR exome

AF:

0.000339

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000159

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000368

AC:

AN:

1330304

Hom.:

Cov.:

AF XY:

0.0000384

AC XY:

AN XY:

650746

show subpopulations

African (AFR)

AF:

0.000335

AC:

AN:

29872

American (AMR)

AF:

0.00

AC:

AN:

26252

Ashkenazi Jewish (ASJ)

AF:

0.0000461

AC:

AN:

21680

East Asian (EAS)

AF:

0.0000807

AC:

AN:

37186

South Asian (SAS)

AF:

0.0000949

AC:

AN:

63202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48780

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4904

European-Non Finnish (NFE)

AF:

0.0000240

AC:

AN:

1043688

Other (OTH)

AF:

0.0000731

AC:

AN:

54740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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

AF:

0.000230

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000548

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000749

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome 9 (1)

Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5435651:COACH syndrome 1 (1)

Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5436837:COACH syndrome 2;C5676970:Retinitis pigmentosa 93 (1)

Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.38

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.4

PhyloP100

5.4

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.47

MVP

0.97

MPC

0.34

ClinPred

0.68

GERP RS

5.7

Varity_R

0.43

gMVP

0.80

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over