rs267607482

chr2-219421340-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001927.4(DES):c.1024A>G(p.Asn342Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N342N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DES NM_001927.4 missense, splice_region
• Scores: Splicing: ADA: 0.6359
• Clinical Significance: Pathogenic criteria provided, single submitter P:4 O:1
• Conservation: PhyloP100: 7.15

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 2-219421340-A-G is Pathogenic according to our data. Variant chr2-219421340-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 66388.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-219421340-A-G is described in Lovd as [Pathogenic]. Variant chr2-219421340-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.1024A>G	p.Asn342Asp	missense_variant, splice_region_variant	6/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.1024A>G	p.Asn342Asp	missense_variant, splice_region_variant	6/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.498A>G		splice_region_variant, non_coding_transcript_exon_variant	5/8	4
DES	ENST00000492726.1	n.419A>G		splice_region_variant, non_coding_transcript_exon_variant	5/6	4
DES	ENST00000683013.1	n.412A>G		splice_region_variant, non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Desmin-related myofibrillar myopathy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2016	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change impairs desmin filamentous network formation and causes cytoplasmic desmin aggregates in vitro (PMID: 22403400, 12609507). This variant has been reported in several families and individuals affected with desmin-related myofibrillar myopathy (PMID: 22215463, 10717012, 12609507, 20423733, 22153487). In one of these families, this variant was shown to arise de novo (PMID: 12609507). ClinVar contains an entry for this variant (Variation ID: 66388). This variant is not present in population databases (rs267607482, ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 342 of the DES protein (p.Asn342Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.89		Loss of MoRF binding (P = 0.0781);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.64
dbscSNV1_RF	Benign	0.68
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

Other links and lift over

dbSNP: rs267607482; hg19: chr2-220286062;