2-219418541-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_001927.4(DES):​c.79G>C​(p.Gly27Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,449,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

DES
NM_001927.4 missense

Scores

1
7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.49
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a region_of_interest Head (size 106) in uniprot entity DESM_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_001927.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DESNM_001927.4 linkc.79G>C p.Gly27Arg missense_variant Exon 1 of 9 ENST00000373960.4 NP_001918.3 P17661Q53SB5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DESENST00000373960.4 linkc.79G>C p.Gly27Arg missense_variant Exon 1 of 9 1 NM_001927.4 ENSP00000363071.3 P17661

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000345
AC:
5
AN:
1449616
Hom.:
0
Cov.:
72
AF XY:
0.00000277
AC XY:
2
AN XY:
720998
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000451
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Desmin-related myofibrillar myopathy Uncertain:1
Jan 16, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DES-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 27 of the DES protein (p.Gly27Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
CardioboostCm
Benign
0.014
BayesDel_addAF
Uncertain
0.087
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T
Eigen
Benign
-0.037
Eigen_PC
Benign
0.17
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.80
T
M_CAP
Uncertain
0.20
D
MetaRNN
Uncertain
0.49
T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
0.81
L
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.72
N
REVEL
Uncertain
0.38
Sift
Benign
0.056
T
Sift4G
Benign
0.23
T
Polyphen
0.010
B
Vest4
0.67
MutPred
0.38
Loss of relative solvent accessibility (P = 0.0306);
MVP
0.92
MPC
1.1
ClinPred
0.83
D
GERP RS
5.1
Varity_R
0.11
gMVP
0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-220283263; API