rs397516689

Variant names:

• chr2-219418589-A-G
• rs397516689
• NM_001927.4:c.127A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001927.4(DES):​c.127A>G​(p.Lys43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K43T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 uncertain in NM_001927.4
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23812222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.127A>G	p.Lys43Glu	missense_variant	Exon 1 of 9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.127A>G	p.Lys43Glu	missense_variant	Exon 1 of 9	1	NM_001927.4	ENSP00000363071.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 92

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 31, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Lys43Glu variant in DES has not been reported in the literature, but has bee n identified in 1 individual with DCM tested by our laboratory. Computational an alyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen, an d SIFT) do not provide strong support for or against an impact to the protein. A dditional information is needed to fully assess the clinical significance of the Lys43Glu variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
CardioboostCm	Benign	0.026
BayesDel_addAF	Benign	0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.69
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.27
Sift	Benign	0.29	T
Sift4G	Benign	0.42	T
Polyphen		0.22	B
Vest4		0.31
MutPred		0.39		Loss of MoRF binding (P = 0.0041);
MVP		0.90
MPC		1.2
ClinPred		0.46	T
GERP RS		5.1
PromoterAI		0.025	Neutral
Varity_R		0.57
gMVP		0.63
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs397516689; hg19: chr2-220283311; COSMIC: COSV100900336; COSMIC: COSV100900336;