rs75882680

Variant names:

• chr2-219420280-T-C
• rs75882680
• NM_001927.4:c.669T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001927.4(DES):​c.669T>C​(p.Ile223Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,614,180 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (171 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (144 hom.)
• Consequence: DES NM_001927.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.155
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-219420280-T-C is Benign according to our data. Variant chr2-219420280-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.155 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0878 is higher than 0.05.

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.669T>C	p.Ile223Ile	synonymous	Exon 3 of 9	NP_001918.3
	DES	NM_001382708.1		c.666T>C	p.Ile222Ile	synonymous	Exon 3 of 9	NP_001369637.1
	DES	NM_001382712.1		c.669T>C	p.Ile223Ile	synonymous	Exon 3 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.669T>C	p.Ile223Ile	synonymous	Exon 3 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.669T>C	p.Ile223Ile	synonymous	Exon 3 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.669T>C	p.Ile223Ile	synonymous	Exon 3 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4030 AN: 152170 Hom.: 171 Cov.: 32

Gnomad AFR AF: 0.0903

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.00745 AC: 1873 AN: 251462 AF XY: 0.00561

Gnomad AFR exome AF: 0.0911

Gnomad AMR exome AF: 0.00682

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000914

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00321 AC: 4694 AN: 1461892 Hom.: 144 Cov.: 35 AF XY: 0.00275 AC XY: 2000 AN XY: 727246

African (AFR) AF: 0.0910 AC: 3047 AN: 33480

American (AMR) AF: 0.00749 AC: 335 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.000720 AC: 801 AN: 1112012

Other (OTH) AF: 0.00694 AC: 419 AN: 60396

GnomAD4 genome AF: 0.0265 AC: 4036 AN: 152288 Hom.: 171 Cov.: 32 AF XY: 0.0254 AC XY: 1894 AN XY: 74474

African (AFR) AF: 0.0902 AC: 3746 AN: 41548

American (AMR) AF: 0.0113 AC: 173 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68028

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.0125 Hom.: 38

Bravo AF: 0.0301

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00136

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	2	Cardiomyopathy (2)
-	-	2	Desmin-related myofibrillar myopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1I (1)
-	-	1	Myofibrillar Myopathy, Dominant (1)
-	-	1	Neurogenic scapuloperoneal syndrome, Kaeser type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=93/7	polymorphism (auto)

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: rs75882680; hg19: chr2-220285002;