rs751942358

Variant names:

• chr2-219421559-C-G
• rs751942358
• NM_001927.4:c.1243C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-219421559-C-G
• chr2-219421559-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001927.4(DES):​c.1243C>G​(p.Arg415Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R415Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DES NM_001927.4 missense, splice_region
• Scores: Splicing: ADA: 0.002415
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.474
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001927.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	NM_001927.4	MANE Select	c.1243C>G	p.Arg415Gly	missense splice_region	Exon 6 of 9	NP_001918.3
	DES	NM_001382708.1		c.1240C>G	p.Arg414Gly	missense splice_region	Exon 6 of 9	NP_001369637.1
	DES	NM_001382712.1		c.1243C>G	p.Arg415Gly	missense splice_region	Exon 6 of 9	NP_001369641.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	ENST00000373960.4	TSL:1 MANE Select	c.1243C>G	p.Arg415Gly	missense splice_region	Exon 6 of 9	ENSP00000363071.3
	DES	ENST00000477226.6	TSL:4	n.717C>G		splice_region non_coding_transcript_exon	Exon 5 of 8
	DES	ENST00000492726.1	TSL:4	n.638C>G		splice_region non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desmin-related myofibrillar myopathy Uncertain:1

Feb 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 415 of the DES protein (p.Arg415Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DES-related conditions. ClinVar contains an entry for this variant (Variation ID: 1058593). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.

not provided Uncertain:1

Aug 05, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	0.12
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		0.47
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.72		Gain of glycosylation at S414 (P = 0.05)
MVP		0.95
MPC		1.7
ClinPred		1.0	D
GERP RS		0.46
Varity_R		0.92
gMVP		0.96
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.020		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: rs751942358; hg19: chr2-220286281;