chr2-219421542-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_001927.4(DES):c.1226T>C(p.Leu409Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L409L) has been classified as Likely benign.
Frequency
Consequence
NM_001927.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.1226T>C | p.Leu409Pro | missense_variant | 6/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.1226T>C | p.Leu409Pro | missense_variant | 6/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.700T>C | non_coding_transcript_exon_variant | 5/8 | 4 | ||||
DES | ENST00000492726.1 | n.621T>C | non_coding_transcript_exon_variant | 5/6 | 4 | ||||
DES | ENST00000683013.1 | n.614T>C | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 07, 2011 | Variant classified as Uncertain Significance - Favor Pathogenic. The Leu409Pro v ariant has not been reported in the literature and has not been previously detec ted in over 254 Caucasian probands tested by our laboratory. Leucine (Leu) at p osition 409 is conserved across mammals and frogs, increasing the likelihood tha t the change is pathogenic. In addition, computational analyses (PolyPhen2, SIFT , AlignGVGD) suggest that the Leu409Pro variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, evolutionary conservation and computational predictions support a pathogenic rol e but additional studies are necessary to determine the clinical significance of the Leu409Pro variant with certainty. Please note: Desmin variants are assoc iated with a variable clinical phenotype referred to as desmin-related myopathy (OMIM #601419) or myofibrillar myopathy, which can manifest as isolated myopathy (proximal or distal) or isolated cardiomyopathies (including DCM and RCM). Sen sory symptoms (muscle stiffness, aching, and cramps) are present in a small port ion of individuals. Peripheral neuropathy is present in about 20% and cardiomyop athy in 15%-30% of affected individuals. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at