2-26456481-T-TCCTC
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_145038.5(DRC1):c.2190_2193dup(p.Thr732SerfsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.000282 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00028 ( 0 hom. )
Consequence
DRC1
NM_145038.5 frameshift
NM_145038.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.74
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 Uncertain_significance. Variant got 4 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0162 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| DRC1 | NM_145038.5 | c.2190_2193dup | p.Thr732SerfsTer18 | frameshift_variant | 17/17 | ENST00000288710.7 | |
| DRC1 | XM_047446339.1 | c.1170_1173dup | p.Thr392SerfsTer18 | frameshift_variant | 10/10 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DRC1 | ENST00000288710.7 | c.2190_2193dup | p.Thr732SerfsTer18 | frameshift_variant | 17/17 | 2 | NM_145038.5 | P1 | |
| DRC1 | ENST00000649059.1 | c.*1153_*1156dup | 3_prime_UTR_variant, NMD_transcript_variant | 16/16 |
Frequencies
GnomAD3 genomes 0.000342 AC: 52AN: 152168Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000179 AC: 45AN: 251274Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135824
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GnomAD4 exome AF: 0.000276 AC: 403AN: 1461850Hom.: 0 Cov.: 30 AF XY: 0.000256 AC XY: 186AN XY: 727232
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GnomAD4 genome 0.000342 AC: 52AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 21 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 14, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 18, 2016 | - - |
Primary ciliary dyskinesia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change creates a premature translational stop signal (p.Thr732Serfs*18) in the DRC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the DRC1 protein. This variant is present in population databases (rs763631774, 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: 525352). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2022 | Frameshift variant predicted to result in protein modification as the last 9 amino acids are replaced with 17 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at