rs374356079
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_016008.4(DYNC2LI1):c.993+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000221 in 1,587,092 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 Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
DYNC2LI1
NM_016008.4 splice_donor
NM_016008.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.80
Genes affected
DYNC2LI1 (HGNC:24595): (dynein cytoplasmic 2 light intermediate chain 1) This gene encodes a protein that is a component of the dynein-2 microtubule motor protein complex that plays a role in the retrograde transport of cargo in primary cilia via the intraflagellar transport system. This gene is ubiquitously expressed and its protein, which localizes to the axoneme and Golgi apparatus, interacts directly with the cytoplasmic dynein 2 heavy chain 1 protein to form part of the multi-protein dynein-2 complex. Mutations in this gene produce defects in the dynein-2 complex which result in several types of ciliopathy including short-rib thoracic dysplasia 15 with polydactyly (SRTD15). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.08712121 fraction of the gene. Cryptic splice site detected, with MaxEntScore 2, offset of -46, new splice context is: tcaGTatgc. 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;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 2-43805247-G-A is Pathogenic according to our data. Variant chr2-43805247-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2LI1 | NM_016008.4 | c.993+1G>A | splice_donor_variant | ENST00000260605.12 | |||
DYNC2LI1 | NM_001193464.2 | c.996+1G>A | splice_donor_variant | ||||
DYNC2LI1 | NM_001348912.2 | c.993+1G>A | splice_donor_variant | ||||
DYNC2LI1 | NM_001348913.2 | c.996+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2LI1 | ENST00000260605.12 | c.993+1G>A | splice_donor_variant | 1 | NM_016008.4 | P4 | |||
DYNC2LI1 | ENST00000605786.5 | c.996+1G>A | splice_donor_variant | 1 | A1 | ||||
DYNC2LI1 | ENST00000378587.3 | c.946G>A | p.Val316Ile | missense_variant | 11/11 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248506Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134286
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GnomAD4 exome AF: 0.0000237 AC: 34AN: 1434956Hom.: 0 Cov.: 24 AF XY: 0.0000182 AC XY: 13AN XY: 715496
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Asphyxiating thoracic dystrophy 1 Pathogenic:1
Pathogenic, no assertion criteria provided | research | David Geffen School of Medicine, University of California, Los Angeles | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2021 | ClinVar contains an entry for this variant (Variation ID: 212764). Disruption of this splice site has been observed in individual(s) with short rib polydactyly syndrome (PMID: 26077881). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs374356079, gnomAD 0.005%). This sequence change affects a donor splice site in intron 12 of the DYNC2LI1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. Studies have shown that disruption of this splice site alters DYNC2LI1 gene expression (PMID: 26077881). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 26077881). - |
Short-rib thoracic dysplasia 15 with polydactyly Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 16, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at