rs199768782

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001378615.1(CC2D2A):​c.2161C>A​(p.Pro721Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,549,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P721S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

10
8
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.64
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-15540994-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CC2D2ANM_001378615.1 linkc.2161C>A p.Pro721Thr missense_variant 17/37 ENST00000424120.6 NP_001365544.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CC2D2AENST00000424120.6 linkc.2161C>A p.Pro721Thr missense_variant 17/375 NM_001378615.1 ENSP00000403465.1 Q9P2K1-4

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152098
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000643
AC:
1
AN:
155590
Hom.:
0
AF XY:
0.0000122
AC XY:
1
AN XY:
82106
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000445
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000215
AC:
3
AN:
1397468
Hom.:
0
Cov.:
30
AF XY:
0.00000145
AC XY:
1
AN XY:
689176
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000253
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152098
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.39
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D;.
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Uncertain
2.7
M;M
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-6.1
D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.95
MutPred
0.74
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.97
MPC
0.32
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.84
gMVP
0.73

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.

Other links and lift over

dbSNP: rs199768782; hg19: chr4-15542617; COSMIC: COSV67502549; COSMIC: COSV67502549; API