Variant chr2-219418539-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001927.4(DES):c.77T>A(p.Leu26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DES
NM_001927.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.579

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 3 ACMG points.

PM1

In a region_of_interest Head (size 106) in uniprot entity DESM_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_001927.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39610925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4 linkuse as main transcript	c.77T>A	p.Leu26His	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.77T>A	p.Leu26His	missense_variant	1/9	1	NM_001927.4	ENSP00000363071	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000446

AC:

AN:

224444

Hom.:

AF XY:

0.00000802

AC XY:

AN XY:

124718

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:

0.0000101

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449980

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721200

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:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000472

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Jan 13, 2022	This missense variant results in a substitution of leucine with histidine at codon 26 of the DES gene (transcript NM_001927.3). This variant has been reported in ClinVar (423612) NM_001927.4 (DES):c.77T>A (p.Leu26His) and occurred once in GnomAD with a total MAF of 0.0004% and highest MAF of 0.0010% in the European population. This position is conserved. In silico functional algorithms conflict, predicting it as benign (REVEL), tolerated (SIFT), and possibly damaging (PolyPhen), but no functional studies were performed to confirm these predictions. The variant has not occurred in the literature associated with the disease. In conclusion, the available evidence is insufficient to determine the pathogenicity of this variant. Therefore, it is classified as a Variant of Uncertain Significance. -

Desmin-related myofibrillar myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 29, 2023

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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES protein function. ClinVar contains an entry for this variant (Variation ID: 423612). This variant has not been reported in the literature in individuals affected with DES-related conditions. 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 sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 26 of the DES protein (p.Leu26His). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2017

A variant of uncertain significance has been identified in the DES gene. The L26H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L26H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostCm

Benign

0.0030

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.20

Eigen

Benign

0.054

Eigen_PC

Benign

0.077

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.46

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.40

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.95

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.10

REVEL

Benign

0.28

Sift

Benign

0.14

Sift4G

Benign

0.53

Polyphen

0.94

Vest4

0.34

MutPred

0.26

Gain of catalytic residue at G27 (P = 0.1572);

MVP

0.95

MPC

1.1

ClinPred

0.27

GERP RS

5.1

Varity_R

0.17

gMVP

0.52

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

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