rs372825868

Variant names:

• chr2-219418632-C-T
• rs372825868
• NM_001927.4:c.170C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-219418632-C-T
• chr2-219418632-C-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_001927.4(DES):​c.170C>T​(p.Ser57Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,599,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S57S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:5
• Conservation: PhyloP100: 3.70
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• 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 1, dilated cardiomyopathy 1I, atrioventricular block, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, familial isolated dilated cardiomyopathy, neurogenic scapuloperoneal syndrome, Kaeser type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19815353).
• BP6: Variant 2-219418632-C-T is Benign according to our data. Variant chr2-219418632-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44254.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000697 (106/152170) while in subpopulation AMR AF = 0.00288 (44/15300). AF 95% confidence interval is 0.0022. There are 0 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.170C>T	p.Ser57Leu	missense	Exon 1 of 9	NP_001918.3
	DES	NM_001382708.1		c.170C>T	p.Ser57Leu	missense	Exon 1 of 9	NP_001369637.1
	DES	NM_001382712.1		c.170C>T	p.Ser57Leu	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.170C>T	p.Ser57Leu	missense	Exon 1 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.170C>T	p.Ser57Leu	missense	Exon 1 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.170C>T	p.Ser57Leu	missense	Exon 1 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152058 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000289 AC: 63 AN: 218216 AF XY: 0.000250

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000749

Gnomad ASJ exome AF: 0.000447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000188

Gnomad OTH exome AF: 0.000752

GnomAD4 exome AF: 0.000123 AC: 178 AN: 1447712 Hom.: 1 Cov.: 92 AF XY: 0.000117 AC XY: 84 AN XY: 718684

African (AFR) AF: 0.00117 AC: 39 AN: 33218

American (AMR) AF: 0.000788 AC: 34 AN: 43134

Ashkenazi Jewish (ASJ) AF: 0.000353 AC: 9 AN: 25482

East Asian (EAS) AF: 0.00 AC: 0 AN: 39326

South Asian (SAS) AF: 0.00 AC: 0 AN: 84300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51086

Middle Eastern (MID) AF: 0.000874 AC: 5 AN: 5718

European-Non Finnish (NFE) AF: 0.0000479 AC: 53 AN: 1105732

Other (OTH) AF: 0.000636 AC: 38 AN: 59716

GnomAD4 genome AF: 0.000697 AC: 106 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.000833 AC XY: 62 AN XY: 74400

African (AFR) AF: 0.00137 AC: 57 AN: 41534

American (AMR) AF: 0.00288 AC: 44 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67970

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000941

ESP6500AA AF: 0.000965 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000186 AC: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	7	1	not provided (8)
-	2	2	not specified (4)
-	2	-	Desmin-related myofibrillar myopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1I (1)
-	-	1	Neurogenic scapuloperoneal syndrome, Kaeser type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostCm	Benign	0.0079
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.077	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.57
Sift	Benign	0.076	T
Sift4G	Uncertain	0.055	T
Polyphen		0.90	P
Vest4		0.65
MVP		0.92
MPC		0.80
ClinPred		0.017	T
GERP RS		5.1
PromoterAI		0.016	Neutral
Varity_R		0.43
gMVP		0.76
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs372825868; hg19: chr2-220283354; COSMIC: COSV99059326; COSMIC: COSV99059326;