chr2-219420151-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_001927.4(DES):​c.635G>C​(p.Arg212Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R212Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DES
NM_001927.4 missense

Scores

16
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.86

Publications

0 publications found
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]
DES Gene-Disease associations (from GenCC):
  • dilated cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • dilated cardiomyopathy 1I
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • myofibrillar myopathy 1
    Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • atrioventricular block
    Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: MODERATE Submitted by: ClinGen
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • neurogenic scapuloperoneal syndrome, Kaeser type
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.7729 (below the threshold of 3.09). Trascript score misZ: 0.36303 (below the threshold of 3.09). GenCC associations: The gene is linked to myofibrillar myopathy 1, dilated cardiomyopathy 1I, atrioventricular block, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, familial isolated dilated cardiomyopathy, neurogenic scapuloperoneal syndrome, Kaeser type.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DESNM_001927.4 linkc.635G>C p.Arg212Pro missense_variant Exon 2 of 9 ENST00000373960.4 NP_001918.3 P17661Q53SB5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DESENST00000373960.4 linkc.635G>C p.Arg212Pro missense_variant Exon 2 of 9 1 NM_001927.4 ENSP00000363071.3 P17661
DESENST00000477226.6 linkn.109G>C non_coding_transcript_exon_variant Exon 1 of 8 4
DESENST00000492726.1 linkn.30G>C non_coding_transcript_exon_variant Exon 1 of 6 4
DESENST00000683013.1 linkn.-73G>C upstream_gene_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461890
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112010
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
CardioboostCm
Uncertain
0.83
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.33
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H
PhyloP100
9.9
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-6.1
D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.97
MutPred
0.89
Loss of disorder (P = 0.1338);
MVP
0.99
MPC
0.0084
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.98
gMVP
0.98
Mutation Taster
=3/97
disease causing

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

Other links and lift over

dbSNP: rs144261171; hg19: chr2-220284873; API