rs1553603267

Variant names:

• chr2-219418896-G-A
• rs1553603267
• NM_001927.4:c.434G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-219418896-G-A
• chr2-219418896-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001927.4(DES):​c.434G>A​(p.Gly145Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,411,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G145G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.7729 (below the threshold of 3.09). Trascript score misZ: 0.36303 (below the threshold of 3.09). GenCC associations: The gene is linked to myofibrillar myopathy, atrioventricular block, arrhythmogenic right ventricular cardiomyopathy, myofibrillar myopathy 1, dilated cardiomyopathy 1I, neurogenic scapuloperoneal syndrome, Kaeser type, familial isolated dilated cardiomyopathy, dilated cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32996243).

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.434G>A	p.Gly145Asp	missense	Exon 1 of 9	NP_001918.3
	DES	NM_001382708.1		c.434G>A	p.Gly145Asp	missense	Exon 1 of 9	NP_001369637.1
	DES	NM_001382712.1		c.434G>A	p.Gly145Asp	missense	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.434G>A	p.Gly145Asp	missense	Exon 1 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.434G>A	p.Gly145Asp	missense	Exon 1 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.434G>A	p.Gly145Asp	missense	Exon 1 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1411070 Hom.: 0 Cov.: 91 AF XY: 0.00 AC XY: 0 AN XY: 697448

African (AFR) AF: 0.00 AC: 0 AN: 32184

American (AMR) AF: 0.00 AC: 0 AN: 36706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.00 AC: 0 AN: 36756

South Asian (SAS) AF: 0.00 AC: 0 AN: 80364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086662

Other (OTH) AF: 0.00 AC: 0 AN: 58580

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Uncertain	0.42
CardioboostCm	Benign	0.0064
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.0066	D
MutationAssessor	Benign	1.4	L
PhyloP100		3.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.34
Sift	Benign	0.093	T
Sift4G	Benign	0.18	T
Polyphen		0.39	B
Vest4		0.32
MutPred		0.48		Loss of MoRF binding (P = 0.0427)
MVP		0.91
MPC		2.2
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.66
gMVP		0.80
Mutation Taster		=42/58	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

dbSNP: rs1553603267; hg19: chr2-220283618;