Genetic Variant CC2D2A:p.Met516Leu (chr4-15533272-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378615.1(CC2D2A):c.1546A>T(p.Met516Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,449,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M516V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.07

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21527493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.1546A>T	p.Met516Leu	missense_variant	Exon 14 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.1546A>T	p.Met516Leu	missense_variant	Exon 14 of 37	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449508

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720412

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32978

American (AMR)

AF:

0.00

AC:

AN:

42076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25784

East Asian (EAS)

AF:

0.00

AC:

AN:

39352

South Asian (SAS)

AF:

0.0000241

AC:

AN:

82902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107474

Other (OTH)

AF:

0.00

AC:

AN:

59946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.066

T;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.036

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;T;.

M_CAP

Benign

0.024

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.6

L;.;L

PhyloP100

5.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.32

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.56

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.41

MutPred

0.60

Loss of catalytic residue at M516 (P = 0.0138);Loss of catalytic residue at M516 (P = 0.0138);Loss of catalytic residue at M516 (P = 0.0138);

MVP

0.68

MPC

0.041

ClinPred

0.71

GERP RS

5.4

Varity_R

0.18

gMVP

0.32

Mutation Taster

=90/10

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over