11-103113678-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001377.3(DYNC2H1):c.337C>T(p.Arg113Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,551,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001377.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.337C>T | p.Arg113Trp | missense_variant | Exon 2 of 90 | NM_001080463.2 | ENSP00000497174.1 | |||
DYNC2H1 | ENST00000375735.7 | c.337C>T | p.Arg113Trp | missense_variant | Exon 2 of 89 | 1 | NM_001377.3 | ENSP00000364887.2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151754Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000150 AC: 3AN: 199800Hom.: 0 AF XY: 0.0000182 AC XY: 2AN XY: 109878
GnomAD4 exome AF: 0.0000143 AC: 20AN: 1399422Hom.: 0 Cov.: 30 AF XY: 0.0000101 AC XY: 7AN XY: 693708
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151754Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74056
ClinVar
Submissions by phenotype
Jeune thoracic dystrophy Pathogenic:2
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not specified Uncertain:1
Variant summary: DYNC2H1 c.337C>T (p.Arg113Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.5e-05 in 199800 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.337C>T has been reported in the literature as a compound heterozygous genotype in trans with a pathogenic variant in an individual with a clinical diagnosis of asphyxiating thoracic dystrophy (Zhang_2018). These data do not allow any strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29068549). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as either VUS (n=2) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Asphyxiating thoracic dystrophy 3 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Short rib-polydactyly syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at