rs200246467
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001386795.1(DTNA):c.1766G>A(p.Arg589His) variant causes a missense change. The variant allele was found at a frequency of 0.000176 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001386795.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DTNA | NM_001386795.1 | c.1766G>A | p.Arg589His | missense_variant | Exon 18 of 23 | ENST00000444659.6 | NP_001373724.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DTNA | ENST00000444659.6 | c.1766G>A | p.Arg589His | missense_variant | Exon 18 of 23 | 5 | NM_001386795.1 | ENSP00000405819.2 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152086Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000179 AC: 45AN: 250934Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135704
GnomAD4 exome AF: 0.000183 AC: 267AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.000206 AC XY: 150AN XY: 727130
GnomAD4 genome AF: 0.000112 AC: 17AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74434
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Variant classified as Uncertain Significance - Favor Benign. The Arg505His varia nt in DTNA has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/8600 European American chromosomes by the NHLBI Exo me Sequencing Project and in 0.2% (3/1324) of chromosomes tested by the ClinSeq project. (http://evs.gs.washington.edu/EVS/; dbSNP rs200246467). Arginine (Arg) at position 505 is not conserved in evolutionarily distant species and the frog and 4 fish species carry a histidine (His) at this position, raising the possibi lity that this change may be tolerated. Additional computational analyses (bioch emical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the protein. While this frequency and la ck of conservation suggests that this variant is more likely benign, it is too l ow to confidently rule out a disease causing role. Additional information is nee ded to fully assess its clinical significance. -
Variant summary: DTNA c.1685G>A (p.Arg562His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250934 control chromosomes, predominantly at a frequency of 0.00069 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 27.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in DTNA causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.1685G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Uncertain:1
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Left ventricular noncompaction 1 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 562 of the DTNA protein (p.Arg562His). This variant is present in population databases (rs200246467, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DTNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 179015). 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 disruptive. 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