2-219420939-G-C

Position:

• chr2-219420939-G-C

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.1009G>C​(p.Ala337Pro) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A337T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 6.20

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 Interaction with NEB (size 147) in uniprot entity DESM_HUMAN there are 50 pathogenic changes around while only 2 benign (96%) 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 chr2-219420939-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 2-219420939-G-C is Pathogenic according to our data. Variant chr2-219420939-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219420939-G-C is described in Lovd as [Pathogenic]. Variant chr2-219420939-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.1009G>C	p.Ala337Pro	missense_variant	5/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1009G>C	p.Ala337Pro	missense_variant	5/9	1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.483G>C		non_coding_transcript_exon_variant	4/8	4
DES	ENST00000492726.1	n.404G>C		non_coding_transcript_exon_variant	4/6	4
DES	ENST00000683013.1	n.397G>C		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

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	Mar 01, 2024	DES: PM1, PM2, PP1:Moderate, PS3:Moderate, PS4:Moderate -

Desmin-related myofibrillar myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1998

- -

Dilated cardiomyopathy 1I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Nov 18, 2019

The c.1009G>C variant has been previously reported in association with skeletal myopathy with familial segregation (PMID: 9697706), and it has a very low frequency (rs59962885). Clinvar has an entry for this variant (Variation ID:16820). Functional study of the variant shows disruptive effect of proline in helical structure of the protein which leads to a loss of normal function (PMID: 16865695). Based on this evidences the c.1009G>C is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.84
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.87		Gain of catalytic residue at A337 (P = 0.0242);
MVP		0.99
MPC		1.7
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.93

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: rs59962885; hg19: chr2-220285661;