Genetic Variant CC2D2A:p.Arg1218Gly (chr4-15574207-C-G) – 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.3652C>G(p.Arg1218Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R1218Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.04

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=0.10886347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.3652C>G	p.Arg1218Gly	missense_variant	Exon 29 of 37	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 link	c.3652C>G	p.Arg1218Gly	missense_variant	Exon 30 of 38		NP_001073991.2	Q9P2K1-4
CC2D2A	NM_001378617.1 link	c.3505C>G	p.Arg1169Gly	missense_variant	Exon 27 of 35		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.3652C>G	p.Arg1218Gly	missense_variant	Exon 29 of 37	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689998

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31592

American (AMR)

AF:

0.00

AC:

AN:

35684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25168

East Asian (EAS)

AF:

0.00

AC:

AN:

35712

South Asian (SAS)

AF:

0.00

AC:

AN:

79216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078690

Other (OTH)

AF:

0.00

AC:

AN:

57980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

0.093

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

D;.

M_CAP

Benign

0.062

MetaRNN

Benign

0.11

T;T

MetaSVM

Uncertain

-0.028

MutationAssessor

Benign

1.2

L;L

PhyloP100

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.28

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.0040

B;B

Vest4

0.25

MutPred

0.50

Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);

MVP

0.72

MPC

0.051

ClinPred

0.17

GERP RS

0.72

Varity_R

0.16

gMVP

0.33

Mutation Taster

=80/20

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