4-15597428-C-T

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.4459C>T(p.Arg1487Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,552,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1487H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.748

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036909282).

BP6

Variant 4-15597428-C-T is Benign according to our data. Variant chr4-15597428-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238281.

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.4459C>T	p.Arg1487Cys	missense	Exon 35 of 37	NP_001365544.1
CC2D2A	NM_001080522.2		c.4459C>T	p.Arg1487Cys	missense	Exon 36 of 38	NP_001073991.2
CC2D2A	NM_001378617.1		c.4312C>T	p.Arg1438Cys	missense	Exon 33 of 35	NP_001365546.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.4459C>T	p.Arg1487Cys	missense	Exon 35 of 37	ENSP00000403465.1
CC2D2A	ENST00000503292.6	TSL:1	c.4459C>T	p.Arg1487Cys	missense	Exon 36 of 38	ENSP00000421809.1
CC2D2A	ENST00000634028.2	TSL:1	n.*17C>T		non_coding_transcript_exon	Exon 32 of 34	ENSP00000488669.2

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

365

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00809

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.000453

AC:

AN:

161232

AF XY:

0.000388

show subpopulations

Gnomad AFR exome

AF:

0.00680

Gnomad AMR exome

AF:

0.000524

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000889

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000243

AC:

340

AN:

1400438

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

147

AN XY:

690930

show subpopulations

African (AFR)

AF:

0.00837

AC:

265

AN:

31670

American (AMR)

AF:

0.000614

AC:

AN:

35854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25224

East Asian (EAS)

AF:

0.0000278

AC:

AN:

35974

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49386

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000927

AC:

AN:

1079268

Other (OTH)

AF:

0.000655

AC:

AN:

58056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00240

AC:

365

AN:

152226

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00806

AC:

335

AN:

41546

American (AMR)

AF:

0.00131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67998

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000811

Hom.:

Bravo

AF:

0.00253

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00575

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000392

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Joubert syndrome 9 (1)

Meckel syndrome, type 6 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.83

M_CAP

Benign

0.029

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.3

PhyloP100

0.75

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.3

REVEL

Benign

0.082

Sift

Benign

0.077

Sift4G

Benign

0.082

Polyphen

0.021

Vest4

0.13

MVP

0.63

MPC

0.054

ClinPred

0.029

GERP RS

2.7

Varity_R

0.075

gMVP

0.48

Mutation Taster

=89/11

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