NM_001927.4:c.15C>A

Variant names:

• chr2-219418477-C-A
• rs1322222685
• NM_001927.4:c.15C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001927.4(DES):​c.15C>A​(p.Tyr5*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DES NM_001927.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59
• 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 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 126 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.15C>A	p.Tyr5*	stop_gained	Exon 1 of 9	NP_001918.3
	DES	NM_001382708.1		c.15C>A	p.Tyr5*	stop_gained	Exon 1 of 9	NP_001369637.1
	DES	NM_001382712.1		c.15C>A	p.Tyr5*	stop_gained	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.15C>A	p.Tyr5*	stop_gained	Exon 1 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.15C>A	p.Tyr5*	stop_gained	Exon 1 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.15C>A	p.Tyr5*	stop_gained	Exon 1 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000452 AC: 1 AN: 221064 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000612

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445662 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 719462

African (AFR) AF: 0.00 AC: 0 AN: 32326

American (AMR) AF: 0.00 AC: 0 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.00 AC: 0 AN: 38630

South Asian (SAS) AF: 0.00 AC: 0 AN: 85358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5064

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108920

Other (OTH) AF: 0.00 AC: 0 AN: 59772

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		1.6
Vest4		0.75
GERP RS		3.2
PromoterAI		-0.077	Neutral
Mutation Taster		=12/188	disease causing (fs/PTC)

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

dbSNP: rs1322222685; hg19: chr2-220283199;