rs61731508

Variant names:

• chr2-219421342-C-T
• rs61731508
• NM_001927.4:c.1026C>T
• DES p.Asn342Asn

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.1026C>T​(p.Asn342Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,016 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (113 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (96 hom.)
• Consequence: DES NM_001927.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -2.25
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-219421342-C-T is Benign according to our data. Variant chr2-219421342-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0655 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.1026C>T	p.Asn342Asn	splice_region synonymous	Exon 6 of 9	NP_001918.3
	DES	NM_001382708.1		c.1023C>T	p.Asn341Asn	splice_region synonymous	Exon 6 of 9	NP_001369637.1
	DES	NM_001382712.1		c.1026C>T	p.Asn342Asn	splice_region synonymous	Exon 6 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.1026C>T	p.Asn342Asn	splice_region synonymous	Exon 6 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.1026C>T	p.Asn342Asn	splice_region synonymous	Exon 6 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.1026C>T	p.Asn342Asn	splice_region synonymous	Exon 6 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2979 AN: 152110 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.0675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00897

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00520 AC: 1307 AN: 251276 AF XY: 0.00365

Gnomad AFR exome AF: 0.0706

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00209 AC: 3054 AN: 1461788 Hom.: 96 Cov.: 31 AF XY: 0.00174 AC XY: 1268 AN XY: 727194

African (AFR) AF: 0.0714 AC: 2391 AN: 33472

American (AMR) AF: 0.00389 AC: 174 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1111956

Other (OTH) AF: 0.00513 AC: 310 AN: 60386

GnomAD4 genome AF: 0.0196 AC: 2988 AN: 152228 Hom.: 113 Cov.: 32 AF XY: 0.0188 AC XY: 1399 AN XY: 74428

African (AFR) AF: 0.0676 AC: 2805 AN: 41514

American (AMR) AF: 0.00896 AC: 137 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68016

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.0103 Hom.: 28

Bravo AF: 0.0223

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	not provided (6)
-	-	2	Desmin-related myofibrillar myopathy (2)
-	-	1	Cardiomyopathy (1)
-	-	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	-0.68
CADD	Benign	0.16
DANN	Benign	0.81
PhyloP100		-2.2
Mutation Taster		=98/2	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

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

Other links and lift over

dbSNP: rs61731508;

hg19: chr2-220286064;