chr2-219418497-C-T

Variant names:

• chr2-219418497-C-T
• rs267607495
• NM_001927.4:c.35C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001927.4(DES):​c.35C>T​(p.Ser12Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S12S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 3.26
• Publications: 9 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• myofibrillar myopathy 1

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• atrioventricular block

  Inheritance: AD, AR 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: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 27 uncertain in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 2-219418497-C-T is Pathogenic according to our data. Variant chr2-219418497-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 66412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	NM_001927.4	MANE Select	c.35C>T	p.Ser12Phe	missense	Exon 1 of 9	NP_001918.3
	DES	NM_001382708.1		c.35C>T	p.Ser12Phe	missense	Exon 1 of 9	NP_001369637.1
	DES	NM_001382712.1		c.35C>T	p.Ser12Phe	missense	Exon 1 of 9	NP_001369641.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	ENST00000373960.4	TSL:1 MANE Select	c.35C>T	p.Ser12Phe	missense	Exon 1 of 9	ENSP00000363071.3
	DES	ENST00000942906.1		c.35C>T	p.Ser12Phe	missense	Exon 1 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.35C>T	p.Ser12Phe	missense	Exon 1 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449890 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 721430

African (AFR) AF: 0.00 AC: 0 AN: 32464

American (AMR) AF: 0.00 AC: 0 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 38630

South Asian (SAS) AF: 0.00 AC: 0 AN: 85470

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 48934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109080

Other (OTH) AF: 0.0000167 AC: 1 AN: 59856

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Desmin-related myofibrillar myopathy (2)
2	-	-	not provided (3)
1	-	-	Primary dilated cardiomyopathy;C0027868:Neuromuscular disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.65		Loss of phosphorylation at S12 (P = 0.013)
MVP		0.98
MPC		1.5
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		-0.029	Neutral
Varity_R		0.94
gMVP		0.87
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs267607495; hg19: chr2-220283219;