rs34337334

chr2-219420864-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001927.4(DES):c.934G>A(p.Asp312Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,694 control chromosomes in the GnomAD database, including 1 homozygotes. 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. D312A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:2 O:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a region_of_interest Interaction with NEB (size 147) in uniprot entity DESM_HUMAN there are 85 pathogenic changes around while only 6 benign (93%) in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03330955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.934G>A	p.Asp312Asn	missense_variant	5/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.934G>A	p.Asp312Asn	missense_variant	5/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.408G>A		non_coding_transcript_exon_variant	4/8	4
DES	ENST00000492726.1	n.329G>A		non_coding_transcript_exon_variant	4/6	4
DES	ENST00000683013.1	n.322G>A		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 151964 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00167

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: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251002 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135682

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000623 AC: 91 AN: 1461612 Hom.: 1 Cov.: 38 AF XY: 0.0000536 AC XY: 39 AN XY: 727126

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152082 Hom.: 0 Cov.: 31 AF XY: 0.000498 AC XY: 37 AN XY: 74342

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.0258 Hom.: 2306

Bravo AF: 0.000627

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Expression studies suggest this variant results in impairment of the desmin filament network (Taylor et al., 2007); however, it is unclear how these studies may translate to a pathogenic role in vivo; This variant is associated with the following publications: (PMID: 22337857, 27896284, 24503780, 23299917, 29988065, 32403337, 34426522, 17325244, 34045587) -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Asp312Asn variant in DES has been reported in 1 Black individual with DCM and in vitro studies suggest that this variant may impact protein function, though these assays may not accurately represent biological function (Taylor 2007). In addition, this variant has been identified by our laboratory in 1 Black individual with infant-onset complex cardiomyopathy a well as 2 members of a Hispanic family (both with DCM). However, this variant is present in 0.2% (7/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs34337334). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Asp312Asn variant is uncertain. ACMG/AMP criteria applied: BA1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2019	- -

Desmin-related myofibrillar myopathy Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 312 of the DES protein (p.Asp312Asn). This variant is present in population databases (rs34337334, gnomAD 0.2%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 17325244, 24503780). ClinVar contains an entry for this variant (Variation ID: 44274). 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. Experimental studies have shown that this missense change affects DES function (PMID: 17325244). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dilated cardiomyopathy 1I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 23, 2015

- -

Desmin-related myofibrillar myopathy;C1858154:Dilated cardiomyopathy 1I;C1867005:Neurogenic scapuloperoneal syndrome, Kaeser type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

May 21, 2021

- -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

-

- -

Neurogenic scapuloperoneal syndrome, Kaeser type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
CardioboostCm	Uncertain	0.51
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.033	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.48
MVP		0.82
MPC		1.4
ClinPred		0.21	T
GERP RS		4.9
Varity_R		0.50
gMVP		0.60

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

Other links and lift over

dbSNP: rs34337334; hg19: chr2-220285586;