rs34365369

Variant names:

• chr2-219418834-G-A
• rs34365369
• NM_001927.4:c.372G>A
• DES p.Glu124Glu

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001927.4(DES):​c.372G>A​(p.Glu124Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,583,166 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (93 hom.)
• Consequence: DES NM_001927.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 2.82
• Publications: 3 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myofibrillar myopathy

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

  Inheritance: SD, AR, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-219418834-G-A is Benign according to our data. Variant chr2-219418834-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0601 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.372G>A	p.Glu124Glu	synonymous	Exon 1 of 9	NP_001918.3
	DES	NM_001382708.1		c.372G>A	p.Glu124Glu	synonymous	Exon 1 of 9	NP_001369637.1
	DES	NM_001382712.1		c.372G>A	p.Glu124Glu	synonymous	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.372G>A	p.Glu124Glu	synonymous	Exon 1 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.372G>A	p.Glu124Glu	synonymous	Exon 1 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.372G>A	p.Glu124Glu	synonymous	Exon 1 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2730 AN: 152214 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.0618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00430 AC: 860 AN: 200182 AF XY: 0.00307

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.00142

Gnomad EAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.00203 AC: 2899 AN: 1430836 Hom.: 93 Cov.: 92 AF XY: 0.00184 AC XY: 1307 AN XY: 708732

African (AFR) AF: 0.0667 AC: 2200 AN: 32972

American (AMR) AF: 0.00366 AC: 145 AN: 39664

Ashkenazi Jewish (ASJ) AF: 0.00110 AC: 28 AN: 25542

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38440

South Asian (SAS) AF: 0.000122 AC: 10 AN: 82024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50786

Middle Eastern (MID) AF: 0.00995 AC: 57 AN: 5726

European-Non Finnish (NFE) AF: 0.000154 AC: 169 AN: 1096392

Other (OTH) AF: 0.00487 AC: 289 AN: 59290

GnomAD4 genome AF: 0.0180 AC: 2747 AN: 152330 Hom.: 76 Cov.: 33 AF XY: 0.0177 AC XY: 1315 AN XY: 74488

African (AFR) AF: 0.0621 AC: 2581 AN: 41582

American (AMR) AF: 0.00686 AC: 105 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68028

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.00940 Hom.: 15

Bravo AF: 0.0204

Asia WGS AF: 0.00607 AC: 22 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	7	not specified (7)
-	-	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	-0.46
CADD	Benign	15
DANN	Uncertain	0.98
PhyloP100		2.8
PromoterAI		-0.10	Neutral
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34365369;

hg19: chr2-220283556;

COSMIC: COSV104688328;

COSMIC: COSV104688328;