12-48904338-T-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_033124.5(CCDC65):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000685 in 1,460,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CCDC65
NM_033124.5 start_lost
NM_033124.5 start_lost
Scores
5
5
5
Clinical Significance
Conservation
PhyloP100: 3.59
Genes affected
CCDC65 (HGNC:29937): (coiled-coil domain containing 65) This gene encodes a sperm tail protein that is highly expressed in adult testis, spermatocytes and spermatids. The protein plays a critical role in the assembly of the nexin-dynein regulatory complex. Mutations in this gene result in primary ciliary dyskinesia. [provided by RefSeq, Nov 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCDC65 | NM_033124.5 | c.2T>A | p.Met1? | start_lost | 1/8 | ENST00000320516.5 | |
CCDC65 | NM_001286957.2 | c.-388T>A | 5_prime_UTR_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCDC65 | ENST00000320516.5 | c.2T>A | p.Met1? | start_lost | 1/8 | 1 | NM_033124.5 | P2 | |
CCDC65 | ENST00000266984.9 | c.2T>A | p.Met1? | start_lost | 1/9 | 5 | A2 | ||
CCDC65 | ENST00000552942.5 | c.2T>A | p.Met1? | start_lost | 1/6 | 5 | |||
CCDC65 | ENST00000547861.5 | c.2T>A | p.Met1? | start_lost, NMD_transcript_variant | 1/8 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460846Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726746
GnomAD4 exome
AF:
AC:
1
AN:
1460846
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
726746
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 27 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 18, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2022 | 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. ClinVar contains an entry for this variant (Variation ID: 1010054). This variant has not been reported in the literature in individuals affected with CCDC65-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CCDC65 mRNA. The next in-frame methionine is located at codon 7. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;N;N
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
0.88
.;.;P
Vest4
MutPred
Gain of catalytic residue at P2 (P = 0);Gain of catalytic residue at P2 (P = 0);Gain of catalytic residue at P2 (P = 0);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at