rs148947510

Variant names:

• chr2-219420865-A-C
• rs148947510
• NM_001927.4:c.935A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-219420865-A-C
• chr2-219420865-A-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_001927.4(DES):​c.935A>C​(p.Asp312Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,613,674 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D312N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 9.32
• Publications: 8 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 -8 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=0.017068505).
• BP6: Variant 2-219420865-A-C is Benign according to our data. Variant chr2-219420865-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44275.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000835 (127/152012) while in subpopulation AFR AF = 0.00289 (120/41476). AF 95% confidence interval is 0.00247. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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.935A>C	p.Asp312Ala	missense	Exon 5 of 9	NP_001918.3
	DES	NM_001382708.1		c.932A>C	p.Asp311Ala	missense	Exon 5 of 9	NP_001369637.1
	DES	NM_001382712.1		c.935A>C	p.Asp312Ala	missense	Exon 5 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.935A>C	p.Asp312Ala	missense	Exon 5 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.935A>C	p.Asp312Ala	missense	Exon 5 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.935A>C	p.Asp312Ala	missense	Exon 5 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes AF: 0.000830 AC: 126 AN: 151894 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000339 AC: 85 AN: 251070 AF XY: 0.000251

Gnomad AFR exome AF: 0.00370

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000143 AC: 209 AN: 1461662 Hom.: 0 Cov.: 38 AF XY: 0.000144 AC XY: 105 AN XY: 727144

African (AFR) AF: 0.00338 AC: 113 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111986

Other (OTH) AF: 0.000348 AC: 21 AN: 60390

GnomAD4 genome AF: 0.000835 AC: 127 AN: 152012 Hom.: 0 Cov.: 31 AF XY: 0.000794 AC XY: 59 AN XY: 74276

African (AFR) AF: 0.00289 AC: 120 AN: 41476

American (AMR) AF: 0.000328 AC: 5 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000406 Hom.: 0

Bravo AF: 0.000846

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	1	Cardiovascular phenotype (2)
-	-	2	not specified (2)
-	-	1	DES-related disorder (1)
-	-	1	Desmin-related myofibrillar myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
CardioboostCm	Benign	0.011
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.069	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.98	D
Vest4		0.49
MVP		0.91
MPC		1.6
ClinPred		0.080	T
GERP RS		4.9
Varity_R		0.61
gMVP		0.71
Mutation Taster		=32/68	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: rs148947510; hg19: chr2-220285587;