2-219425699-C-T

Position:

• chr2-219425699-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_001927.4(DES):​c.1325C>T​(p.Thr442Ile) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 4.86

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 13 ACMG points.

• PM1: In a region_of_interest Interaction with CRYAB (size 15) in uniprot entity DESM_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833
• PP5: Variant 2-219425699-C-T is Pathogenic according to our data. Variant chr2-219425699-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219425699-C-T is described in Lovd as [Pathogenic]. Variant chr2-219425699-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-219425699-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.1325C>T	p.Thr442Ile	missense_variant	8/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1325C>T	p.Thr442Ile	missense_variant	8/9	1	NM_001927.4	ENSP00000363071.3

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, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2018	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -

Desmin-related myofibrillar myopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2018	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects desmin assembly and aggregate formation (PMID: 17221859, 21262226). This variant has been reported to segregate with autosomal dominant cardiac and skeletal myopathy in families (PMID: 17221859, 22153487) and has been reported in several individuals affected with autosomal dominant myofibrillar myopathy and desmin-related myopathy (PMID:18653338, 22215463). ClinVar contains an entry for this variant (Variation ID: 16834). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 442 of the DES protein (p.Thr442Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
CardioboostCm	Benign	0.0077
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.77
Sift	Benign	0.097	T
Sift4G	Benign	0.12	T
Polyphen		0.59	P
Vest4		0.81
MutPred		0.74		Loss of disorder (P = 0.0329);
MVP		0.99
MPC		0.78
ClinPred		0.80	D
GERP RS		4.5
Varity_R		0.16
gMVP		0.83

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: rs121913005; hg19: chr2-220290421;