rs193204571
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_018051.5(DYNC2I1):c.2305G>A(p.Glu769Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,360 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_018051.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYNC2I1 | NM_018051.5 | c.2305G>A | p.Glu769Lys | missense_variant | Exon 18 of 25 | ENST00000407559.8 | NP_060521.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2I1 | ENST00000407559.8 | c.2305G>A | p.Glu769Lys | missense_variant | Exon 18 of 25 | 1 | NM_018051.5 | ENSP00000384290.3 | ||
DYNC2I1 | ENST00000444851.5 | n.1463G>A | non_coding_transcript_exon_variant | Exon 13 of 20 | 1 | ENSP00000392608.1 | ||||
DYNC2I1 | ENST00000467220.1 | n.4104G>A | non_coding_transcript_exon_variant | Exon 13 of 20 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000403 AC: 10AN: 248348Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134666
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461360Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 726902
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Jeune thoracic dystrophy Pathogenic:2
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Asphyxiating thoracic dystrophy 3 Pathogenic:2
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See cases Pathogenic:1
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DYNC2I1-related disorder Pathogenic:1
The DYNC2I1 c.2305G>A variant is predicted to result in the amino acid substitution p.Glu769Lys. This variant has been reported in the homozygous and compound heterozygous state in two individuals affected with DYNC2I1-related disease (Table S2 ISDR Case # R04-477 and R91-028 in Zhang et al. 2018. PubMed ID: 29068549). At PreventionGenetics, we have observed this variant in the homozygous state in two affected patients. This variant is interpreted as pathogenic or likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/446627/). This variant is reported in 0.029% of alleles in individuals of Latino descent in gnomAD. Based on the available evidence, we classify this variant as likely pathogenic. -
Short-rib thoracic dysplasia 8 with or without polydactyly Uncertain:1
This sequence change replaces glutamic acid with lysine at codon 769 of the WDR60 protein (p.Glu769Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs193204571, ExAC 0.04%). This variant has been observed in individual(s) with short-rib thoracic dysplasia (PMID: 29068549, Invitae). ClinVar contains an entry for this variant (Variation ID: 446627). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at