11-103321029-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001080463.2(DYNC2H1):c.11747G>A(p.Gly3916Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,599,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001080463.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.11747G>A | p.Gly3916Asp | missense_variant, splice_region_variant | 82/90 | ENST00000650373.2 | |
DYNC2H1 | NM_001377.3 | c.11726G>A | p.Gly3909Asp | missense_variant, splice_region_variant | 81/89 | ENST00000375735.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.11747G>A | p.Gly3916Asp | missense_variant, splice_region_variant | 82/90 | NM_001080463.2 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.11726G>A | p.Gly3909Asp | missense_variant, splice_region_variant | 81/89 | 1 | NM_001377.3 | P3 | |
DYNC2H1 | ENST00000334267.11 | c.2206-114914G>A | intron_variant | 1 | |||||
DYNC2H1 | ENST00000528670.5 | c.905G>A | p.Gly302Asp | missense_variant, splice_region_variant, NMD_transcript_variant | 9/17 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 151962Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000211 AC: 50AN: 237428Hom.: 0 AF XY: 0.000234 AC XY: 30AN XY: 128420
GnomAD4 exome AF: 0.000152 AC: 220AN: 1447636Hom.: 0 Cov.: 31 AF XY: 0.000156 AC XY: 112AN XY: 718888
GnomAD4 genome AF: 0.000138 AC: 21AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74346
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2022 | Observed with a NEK1 gene variant in a patient with SRP in published literature (Thiel et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21211617, 22795106, 29458881, 22482978, 34426522, 34582081) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 16, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 02, 2015 | - - |
Asphyxiating thoracic dystrophy 3 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 07, 2011 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 12, 2021 | The DYNC2H1 c.11747G>A; p.Gly3916Asp variant (rs201479015) is reported in the literature in an individual who was affected with short-rib polydactyly syndrome; however a second variant was not identified (Thiel 2011). This variant is also reported in ClinVar (Variation ID: 30350) and the general population with an allele frequency of 0.019% (52/268,762 alleles) in the Genome Aggregation Database. The glycine at codon 3916 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.17). Due to limited information, the clinical significance of the p.Gly3916Asp variant is uncertain at this time. - |
Jeune thoracic dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 3916 of the DYNC2H1 protein (p.Gly3916Asp). This variant is present in population databases (rs201479015, gnomAD 0.06%). This missense change has been observed in individual(s) with short-rib polydactyly syndrome (PMID: 21211617). ClinVar contains an entry for this variant (Variation ID: 30350). 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: "Deleterious"; PolyPhen-2: "Benign"; 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