rs201439617

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001378615.1(CC2D2A):c.1837G>A(p.Glu613Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000102 in 1,610,494 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 5.33

Publications

2 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04605204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.1837G>A	p.Glu613Lys	missense_variant	Exon 16 of 37	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.1837G>A	p.Glu613Lys	missense_variant	Exon 16 of 37	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000132

AC:

AN:

242538

AF XY:

0.000107

show subpopulations

Gnomad AFR exome

AF:

0.0000674

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000741

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000637

Gnomad OTH exome

AF:

0.000677

GnomAD4 exome

AF:

0.000101

AC:

148

AN:

1458226

Hom.:

Cov.:

AF XY:

0.0000938

AC XY:

AN XY:

724952

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33408

American (AMR)

AF:

0.0000903

AC:

AN:

44286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.000935

AC:

AN:

39586

South Asian (SAS)

AF:

0.0000704

AC:

AN:

85202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53162

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000648

AC:

AN:

1110470

Other (OTH)

AF:

0.000166

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.000112

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41562

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000774

AC:

AN:

5166

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68034

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000127

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.000116

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jul 19, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The E613K variant in the E613K gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The E613K variant was not observed with any significant frequency in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E613K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret E613K as a variant of unknown significance. -

Joubert syndrome 9

Uncertain:2

Aug 08, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases

Uncertain:1

Mar 22, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1837G>A (p.E613K) alteration is located in exon 17 (coding exon 15) of the CC2D2A gene. This alteration results from a G to A substitution at nucleotide position 1837, causing the glutamic acid (E) at amino acid position 613 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel syndrome, type 6

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.051

T;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.72

T;.

M_CAP

Benign

0.0058

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

PhyloP100

5.3

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.62

N;N

REVEL

Benign

0.097

Sift

Benign

0.36

T;T

Sift4G

Benign

0.84

T;T

Polyphen

0.094

B;B

Vest4

0.23

MVP

0.27

MPC

0.049

ClinPred

0.016

GERP RS

3.7

Varity_R

0.087

gMVP

0.37

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over