2-219418465-G-A

Variant names:

• chr2-219418465-G-A
• NM_001927.4:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001927.4(DES):​c.3G>A​(p.Met1?) variant causes a start lost 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DES NM_001927.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.63
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• myofibrillar myopathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• myofibrillar myopathy 1

  Inheritance: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• atrioventricular block

  Inheritance: AR, AD 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 60 pathogenic variants. Next in-frame start position is after 263 codons. Genomic position: 219420546. Lost 0.557 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219418465-G-A is Pathogenic according to our data. Variant chr2-219418465-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3758249.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	NM_001927.4	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 9	NP_001918.3
	DES	NM_001382708.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 9	NP_001369637.1
	DES	NM_001382712.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 9	NP_001369641.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	ENST00000373960.4	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Desmin-related myofibrillar myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.46	D
PhyloP100		6.6
PROVEAN	Benign	-0.64	N
REVEL	Pathogenic	0.73
Sift	Benign	0.093	T
Sift4G	Benign	0.064	T
Polyphen		0.85	P
Vest4		0.88
MutPred		0.98		Loss of phosphorylation at Y5 (P = 0.1069)
MVP		0.94
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		-0.14	Neutral
Varity_R		0.37
gMVP		0.49
Mutation Taster		=13/187	disease causing

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

Other links and lift over

hg19: chr2-220283187;