chr2-219420267-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 5P and 6B. PM2PM5PP3BP4BP6BS1
The NM_001927.4(DES):c.656C>T(p.Thr219Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,614,218 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T219P) has been classified as Pathogenic.
Frequency
Consequence
NM_001927.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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DES | ENST00000373960.4 | c.656C>T | p.Thr219Ile | missense_variant | Exon 3 of 9 | 1 | NM_001927.4 | ENSP00000363071.3 | ||
DES | ENST00000477226.6 | n.130C>T | non_coding_transcript_exon_variant | Exon 2 of 8 | 4 | |||||
DES | ENST00000492726.1 | n.51C>T | non_coding_transcript_exon_variant | Exon 2 of 6 | 4 | |||||
DES | ENST00000683013.1 | n.44C>T | non_coding_transcript_exon_variant | Exon 1 of 7 |
Frequencies
GnomAD3 genomes AF: 0.000532 AC: 81AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251454Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135910
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461890Hom.: 0 Cov.: 36 AF XY: 0.0000454 AC XY: 33AN XY: 727246
GnomAD4 genome AF: 0.000532 AC: 81AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37AN XY: 74494
ClinVar
Submissions by phenotype
not provided Uncertain:4
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Reported in patients with myopathy and hypertrophic cardiomyopathy who also harbored additional variants in other myopathy- and cardiomyopathy-related genes (PMID: 30323756, 32746448); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26807690, 32746448, 30323756) -
not specified Uncertain:1Benign:1
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Variant classified as Uncertain Significance - Favor Benign. The p.Thr219Ile var iant in DES has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.17% (43/24036) of African chromosomes by the Genom e Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144901 249). Computational prediction tools and conservation analysis do not provide st rong support for or against an impact to the protein. In summary, while the clin ical significance of the p.Thr219Ile variant is uncertain, its frequency suggest s that it is more likely to be benign. -
Cardiomyopathy Uncertain:1
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Desmin-related myofibrillar myopathy Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at