chr2-26402096-T-TC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_145038.5(DRC1):c.109dup(p.Gln37ProfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,612,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
DRC1
NM_145038.5 frameshift
NM_145038.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.21
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 Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 2-26402096-T-TC is Pathogenic according to our data. Variant chr2-26402096-T-TC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 663966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DRC1 | NM_145038.5 | c.109dup | p.Gln37ProfsTer30 | frameshift_variant | 1/17 | ENST00000288710.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DRC1 | ENST00000288710.7 | c.109dup | p.Gln37ProfsTer30 | frameshift_variant | 1/17 | 2 | NM_145038.5 | P1 | |
DRC1 | ENST00000421869.5 | c.109dup | p.Gln37ProfsTer30 | frameshift_variant, NMD_transcript_variant | 1/8 | 1 | |||
DRC1 | ENST00000649059.1 | c.95dup | p.Gln33ProfsTer30 | frameshift_variant, NMD_transcript_variant | 1/16 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000488 AC: 12AN: 245970Hom.: 0 AF XY: 0.0000373 AC XY: 5AN XY: 133924
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 21 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Sep 22, 2022 | This DRC1 frameshift variant (rs750136163) is rare (<0.1%) in a large population dataset (gnomAD: 12/245970 total alleles; 0.0049%; no homozygotes). It has been reported in ClinVar (Variation ID 663966) but has not been reported in the literature, to our knowledge. This frameshift variant results in a premature stop codon in exon 2 of 17, likely leading to nonsense-mediated decay and lack of protein production. We consider c.109dupC in DRC1 to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 25, 2022 | - - |
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Gln37Profs*30) in the DRC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DRC1 are known to be pathogenic (PMID: 23354437, 31960620). This variant is present in population databases (rs750136163, gnomAD 0.03%). 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: 663966). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 18, 2020 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at