rs121913004

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001382709.1(DES):​c.736-2A>C variant causes a splice acceptor, intron 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

DES
NM_001382709.1 splice_acceptor, intron

Scores

17
2
1

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 9.20
Variant links:
Genes affected
DES (HGNC:2770): (desmin) This gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form a stable intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. Mutations in this gene are associated with desmin-related myopathy, a familial cardiac and skeletal myopathy (CSM), and with distal myopathies. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-219421482-A-C is Pathogenic according to our data. Variant chr2-219421482-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 16830.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-219421482-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DESNM_001927.4 linkuse as main transcriptc.1166A>C p.Gln389Pro missense_variant 6/9 ENST00000373960.4 NP_001918.3 P17661Q53SB5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DESENST00000373960.4 linkuse as main transcriptc.1166A>C p.Gln389Pro missense_variant 6/91 NM_001927.4 ENSP00000363071.3 P17661
DESENST00000477226.6 linkuse as main transcriptn.640A>C non_coding_transcript_exon_variant 5/84
DESENST00000492726.1 linkuse as main transcriptn.561A>C non_coding_transcript_exon_variant 5/64
DESENST00000683013.1 linkuse as main transcriptn.554A>C non_coding_transcript_exon_variant 4/7

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Desmin-related myofibrillar myopathy Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2001- -
not provided Other:1
not provided, no classification providedliterature onlyEpithelial Biology; Institute of Medical Biology, Singapore-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.1
H
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-5.3
D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.98
MutPred
0.89
Loss of phosphorylation at Y388 (P = 0.1139);
MVP
0.99
MPC
1.6
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.95
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913004; hg19: chr2-220286204; API