2-219423787-C-T

Position:

• chr2-219423787-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001927.4(DES):​c.1255C>T​(p.Pro419Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P419R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 6.65

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a region_of_interest Tail (size 57) in uniprot entity DESM_HUMAN there are 27 pathogenic changes around while only 2 benign (93%) in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-219423788-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 2-219423787-C-T is Pathogenic according to our data. Variant chr2-219423787-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219423787-C-T is described in Lovd as [Pathogenic]. Variant chr2-219423787-C-T is described in Lovd as [Pathogenic]. Variant chr2-219423787-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.1255C>T	p.Pro419Ser	missense_variant	7/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1255C>T	p.Pro419Ser	missense_variant	7/9	1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.729C>T		non_coding_transcript_exon_variant	6/8	4
DES	ENST00000492726.1	n.650C>T		non_coding_transcript_exon_variant	6/6	4
DES	ENST00000683013.1	n.643C>T		non_coding_transcript_exon_variant	5/7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desmin-related myofibrillar myopathy Pathogenic:4

Pathogenic, no assertion criteria provided	research	Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	Feb 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2019	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change forms filaments and does not induce aggregation in cell lines (PMID: 23032110). This variant has been observed to segregate with autosomal dominant desminopathies in several families (PMID:17418574, 22153487, 22395865, 26431784). ClinVar contains an entry for this variant (Variation ID: 39718). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 419 of the DES protein (p.Pro419Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.P419S in DES (NM_001927.4) has been previously reported in multiple patients with autosomal dominant desminopathies (Olivé M et al,Wahbi K et al). Functional studies reveal a damaging effect (Brodehl A et al). The variant has been submitted to ClinVar as Pathogenic.The p.P419S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and serine. The p.P419S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 419 of DES is conserved in all mammalian species. The nucleotide c.1255 in DES is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 07, 2016	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
CardioboostCm	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.72
Sift	Benign	0.074	T
Sift4G	Benign	0.069	T
Polyphen		0.77	P
Vest4		0.92
MutPred		0.82		Loss of catalytic residue at N417 (P = 0.1002);
MVP		0.95
MPC		0.88
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.32
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs62635763; hg19: chr2-220288509; COSMIC: COSV100900438; COSMIC: COSV100900438;