4-15601414-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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:4

Conservation

PhyloP100: 5.38

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CC2D2A	NM_001378615.1 linkuse as main transcript	c.4852C>T	p.Arg1618Cys	missense_variant	37/37	ENST00000424120.6
CC2D2A	NM_001080522.2 linkuse as main transcript	c.4852C>T	p.Arg1618Cys	missense_variant	38/38
CC2D2A	NM_001378617.1 linkuse as main transcript	c.4705C>T	p.Arg1569Cys	missense_variant	35/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.4852C>T	p.Arg1618Cys	missense_variant	37/37	5	NM_001378615.1	P1	Q9P2K1-4

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

GnomAD3 exomes

AF:

0.0000694

AC:

AN:

158472

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

85912

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 SAS exome

AF:

0.000234

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

Gnomad4 AFR exome

AF:

0.000335

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000461

Gnomad4 EAS exome

AF:

0.0000807

Gnomad4 SAS exome

AF:

0.0000949

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000240

Gnomad4 OTH exome

AF:

0.0000731

GnomAD4 genome

AF:

0.000230

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000541

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

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1618 of the CC2D2A protein (p.Arg1618Cys). This variant is present in population databases (rs201219078, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 238282). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CC2D2A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Joubert syndrome 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 03, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Uncertain

0.080

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;.

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.38

T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.47

MVP

0.97

MPC

0.34

ClinPred

0.68

GERP RS

5.7

Varity_R

0.43

gMVP

0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over