rs745800344
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_145038.5(DRC1):c.1029-1G>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000341 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
DRC1
NM_145038.5 splice_acceptor
NM_145038.5 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.57
Genes affected
DRC1 (HGNC:24245): (dynein regulatory complex subunit 1) This gene encodes a central component of the nexin-dynein complex (N-DRC), which regulates the assembly of ciliary dynein. Mutations in this gene can cause ciliary dyskinesia. [provided by RefSeq, Aug 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.060278904 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.2, offset of -31, new splice context is: acataataccttctattcAGctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-26444221-G-T is Pathogenic according to our data. Variant chr2-26444221-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 454974.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DRC1 | NM_145038.5 | c.1029-1G>T | splice_acceptor_variant | ENST00000288710.7 | NP_659475.2 | |||
DRC1 | XM_047446339.1 | c.9-1G>T | splice_acceptor_variant | XP_047302295.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DRC1 | ENST00000288710.7 | c.1029-1G>T | splice_acceptor_variant | 2 | NM_145038.5 | ENSP00000288710 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251246Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135812
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GnomAD4 exome AF: 0.0000369 AC: 54AN: 1461748Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 727174
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 12, 2023 | This sequence change affects an acceptor splice site in intron 8 of the DRC1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DRC1 are known to be pathogenic (PMID: 23354437, 31960620). This variant is present in population databases (rs745800344, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DRC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 454974). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at