rs587777065
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_018051.5(DYNC2I1):c.2246C>T(p.Thr749Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,610,156 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T749S) has been classified as Uncertain significance.
Frequency
Consequence
NM_018051.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2I1 | NM_018051.5 | c.2246C>T | p.Thr749Met | missense_variant | 17/25 | ENST00000407559.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2I1 | ENST00000407559.8 | c.2246C>T | p.Thr749Met | missense_variant | 17/25 | 1 | NM_018051.5 | P1 | |
DYNC2I1 | ENST00000444851.5 | c.1404C>T | p.His468= | synonymous_variant, NMD_transcript_variant | 12/20 | 1 | |||
DYNC2I1 | ENST00000467220.1 | n.4045C>T | non_coding_transcript_exon_variant | 12/20 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152186Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1457970Hom.: 0 Cov.: 31 AF XY: 0.0000221 AC XY: 16AN XY: 724548
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Short-rib thoracic dysplasia 8 with or without polydactyly Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 749 of the WDR60 protein (p.Thr749Met). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with short-rib thoracic dysplasia (PMID: 23910462). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88645). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects WDR60 function (PMID: 30320547). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 05, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at