2-219418712-G-A

Position:

chr2-219418712-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The ENST00000373960.4(DES):c.250G>A(p.Gly84Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000997 in 1,564,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. G84G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

DES
ENST00000373960.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 3.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a region_of_interest Head (size 106) in uniprot entity DESM_HUMAN there are 24 pathogenic changes around while only 2 benign (92%) in ENST00000373960.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2356554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4 linkuse as main transcript	c.250G>A	p.Gly84Ser	missense_variant	1/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4 linkuse as main transcript	c.250G>A	p.Gly84Ser	missense_variant	1/9	1	NM_001927.4	ENSP00000363071	P1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000993

AC:

AN:

171168

Hom.:

AF XY:

0.0000876

AC XY:

AN XY:

91330

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:

0.0000618

Gnomad NFE exome

AF:

0.000217

Gnomad OTH exome

AF:

0.000216

GnomAD4 exome

AF:

0.000101

AC:

143

AN:

1412812

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

698170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000396

Gnomad4 EAS exome

AF:

0.0000268

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000203

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.0000683

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000145

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000356

AC:

ExAC

AF:

0.0000871

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2017	The Gly84Ser variant in the DES gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly84Ser results in a non-conservative amino acid substitution of a non-polar Glycine residue with a polar Serine residue at a position that is not conserved across species. The Gly84Ser variant was not observed with any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. With the clinical and molecular information available at this time, we cannot definitively determine if Gly84Ser is a disease-causing mutation or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2023	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 26, 2013	Variant classified as Uncertain Significance - Favor Benign. The Gly84Ser varian t in DES has not been previously reported in individuals with cardiomyopathy, bu t has been identified in 3/8434 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200545412). Glyc ine (Gly) at position 84 is not well conserved, with two mammals (dog and eleph ant) having this variant (Ser) at this position, which suggests that it is likel y tolerated. Computational analyses (amino acid biochemical properties, SIFT, Po lyPhen-2, AlignGVGD) do not provide strong support for or against an impact to t he protein. In summary, the clinical significance of this variant cannot be dete rmined with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2023	Variant summary: DES c.250G>A (p.Gly84Ser) results in a non-conservative amino acid change located in the Intermediate filament head, DNA-binding domain (IPR006821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 171168 control chromosomes (gnomAD). The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.250G>A has been reported in the literature in an individual from a Cardiomyopathy cohort, however authors classified the variant as VUS (example: Sepp_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35626289). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Desmin-related myofibrillar myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 84 of the DES protein (p.Gly84Ser). This variant is present in population databases (rs200545412, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DES-related conditions. ClinVar contains an entry for this variant (Variation ID: 163024). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DES protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Aug 01, 2022

The p.G84S variant (also known as c.250G>A), located in coding exon 1 of the DES gene, results from a G to A substitution at nucleotide position 250. The glycine at codon 84 is replaced by serine, an amino acid with similar properties. This variant was described in a proband with hypertrophic cardiomyopathy (HCM) and left ventricular non-compaction (LVNC), who also had a TMEM43 variant detected, while his daughter, also with both variants, had LVNC and congenital heart defects; in addition, two family members with HCM had only the p.G84S variant detected (Arbustini E et al. J Am Coll Cardiol, 2016 08;68:949-66). This variant was also detected in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) from a genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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

0.091

CardioboostCm

Benign

0.0043

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.080

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.69

M_CAP

Benign

0.064

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.010

REVEL

Benign

0.28

Sift

Benign

0.88

Sift4G

Benign

0.49

Polyphen

0.95

Vest4

0.23

MVP

0.86

MPC

1.3

ClinPred

0.25

GERP RS

2.7

Varity_R

0.038

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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