rs190698163

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001378615.1(CC2D2A):c.2050T>A(p.Leu684Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,596,822 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.126

Publications

3 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0090070665).

BP6

Variant 4-15540883-T-A is Benign according to our data. Variant chr4-15540883-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194819.

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
CC2D2A	NM_001378615.1	MANE Select	c.2050T>A	p.Leu684Ile	missense	Exon 17 of 37	NP_001365544.1
CC2D2A	NM_001080522.2		c.2050T>A	p.Leu684Ile	missense	Exon 18 of 38	NP_001073991.2
CC2D2A	NM_001378617.1		c.1903T>A	p.Leu635Ile	missense	Exon 15 of 35	NP_001365546.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.2050T>A	p.Leu684Ile	missense	Exon 17 of 37	ENSP00000403465.1
CC2D2A	ENST00000503292.6	TSL:1	c.2050T>A	p.Leu684Ile	missense	Exon 18 of 38	ENSP00000421809.1
CC2D2A	ENST00000513811.5	TSL:1	n.2230T>A		non_coding_transcript_exon	Exon 17 of 18

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

228

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00509

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000389

AC:

AN:

221170

AF XY:

0.000303

show subpopulations

Gnomad AFR exome

AF:

0.00544

Gnomad AMR exome

AF:

0.000348

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:

0.000540

GnomAD4 exome

AF:

0.000202

AC:

292

AN:

1444522

Hom.:

Cov.:

AF XY:

0.000159

AC XY:

114

AN XY:

716562

show subpopulations

African (AFR)

AF:

0.00736

AC:

244

AN:

33142

American (AMR)

AF:

0.000424

AC:

AN:

42498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25800

East Asian (EAS)

AF:

0.00

AC:

AN:

39066

South Asian (SAS)

AF:

0.0000242

AC:

AN:

82682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1103400

Other (OTH)

AF:

0.000418

AC:

AN:

59816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.00150

AC:

229

AN:

152300

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00510

AC:

212

AN:

41568

American (AMR)

AF:

0.000850

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000491

Hom.:

Bravo

AF:

0.00187

ESP6500AA

AF:

0.00433

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000406

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

CC2D2A-related disorder (1)

Inborn genetic diseases (1)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.40

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.062

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.72

M_CAP

Benign

0.0025

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

PhyloP100

0.13

PrimateAI

Benign

0.41

PROVEAN

Benign

0.13

REVEL

Benign

0.040

Sift

Benign

1.0

Sift4G

Benign

0.67

Polyphen

0.048

Vest4

0.45

MVP

0.20

MPC

0.046

ClinPred

0.0069

GERP RS

-2.8

Varity_R

0.029

gMVP

0.18

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over