Variant chr2-219425735-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_001927.4(DES):c.1361G>A(p.Arg454Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000482 in 1,452,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R454W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DES
NM_001927.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.65

Variant links:

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 links:

DES (HGNC:):

DES links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a region_of_interest Tail (size 57) in uniprot entity DESM_HUMAN there are 27 pathogenic changes around while only 2 benign (93%) in NM_001927.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-219425734-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4 linkuse as main transcript	c.1361G>A	p.Arg454Gln	missense_variant	8/9	ENST00000373960.4	NP_001918.3	P17661Q53SB5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4 linkuse as main transcript	c.1361G>A	p.Arg454Gln	missense_variant	8/9	1	NM_001927.4	ENSP00000363071.3		P17661

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000128

AC:

AN:

234226

Hom.:

AF XY:

0.00000793

AC XY:

AN XY:

126076

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000284

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000482

AC:

AN:

1452328

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721412

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000632

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000826

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2017	- -

Desmin-related myofibrillar myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 454 of the DES protein (p.Arg454Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 191616). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant disrupts the p.Arg454 amino acid residue in DES. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17221859, 22153487, 25557463). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The p.R454Q variant (also known as c.1361G>A), located in coding exon 8 of the DES gene, results from a G to A substitution at nucleotide position 1361. The arginine at codon 454 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort, and has been detected in a dilated cardiomyopathy cohort; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Haas J et al. Eur Heart J, 2015 May;36:1123-35a). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

CardioboostCm

Uncertain

0.66

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.65

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.80

Sift

Benign

0.034

Sift4G

Benign

0.074

Polyphen

0.95

Vest4

0.57

MutPred

0.65

Loss of catalytic residue at R454 (P = 0.0479);

MVP

0.99

MPC

0.72

ClinPred

0.97

GERP RS

4.5

Varity_R

0.25

gMVP

0.91

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over