2-219420154-C-T

Position:

chr2-219420154-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001927.4(DES):c.638C>T(p.Ala213Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,216 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A213A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0099 ( 12 hom., cov: 32)

Exomes 𝑓: 0.015 ( 221 hom. )

Consequence

DES
NM_001927.4 missense, splice_region

Scores

Splicing: ADA: 0.05342

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:22O:1

Conservation

PhyloP100: 1.51

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013873875).

BP6

Variant 2-219420154-C-T is Benign according to our data. Variant chr2-219420154-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44265.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=10, not_provided=1, Uncertain_significance=1}. Variant chr2-219420154-C-T is described in Lovd as [Benign]. Variant chr2-219420154-C-T is described in Lovd as [Likely_benign]. Variant chr2-219420154-C-T is described in Lovd as [Pathogenic]. Variant chr2-219420154-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00989 (1506/152346) while in subpopulation NFE AF= 0.0158 (1077/68030). AF 95% confidence interval is 0.015. There are 12 homozygotes in gnomad4. There are 663 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4 linkuse as main transcript	c.638C>T	p.Ala213Val	missense_variant, splice_region_variant	2/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DES	ENST00000373960.4 linkuse as main transcript	c.638C>T	p.Ala213Val	missense_variant, splice_region_variant	2/9	1	NM_001927.4	ENSP00000363071	P1
DES	ENST00000477226.6 linkuse as main transcript	n.112C>T		splice_region_variant, non_coding_transcript_exon_variant	1/8	4
DES	ENST00000492726.1 linkuse as main transcript	n.33C>T		splice_region_variant, non_coding_transcript_exon_variant	1/6	4

Frequencies

GnomAD3 genomes

AF:

0.00989

AC:

1505

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00321

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.00942

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00904

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0158

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00921

AC:

2315

AN:

251474

Hom.:

AF XY:

0.00996

AC XY:

1354

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00575

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00340

Gnomad FIN exome

AF:

0.00734

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.00896

GnomAD4 exome

AF:

0.0146

AC:

21307

AN:

1461870

Hom.:

221

Cov.:

AF XY:

0.0142

AC XY:

10361

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00263

Gnomad4 AMR exome

AF:

0.00617

Gnomad4 ASJ exome

AF:

0.00157

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00345

Gnomad4 FIN exome

AF:

0.00889

Gnomad4 NFE exome

AF:

0.0174

Gnomad4 OTH exome

AF:

0.0130

GnomAD4 genome

AF:

0.00989

AC:

1506

AN:

152346

Hom.:

Cov.:

AF XY:

0.00890

AC XY:

663

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00320

Gnomad4 AMR

AF:

0.00934

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.00904

Gnomad4 NFE

AF:

0.0158

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.0136

Hom.:

Bravo

AF:

0.00963

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0137

AC:

118

ExAC

AF:

0.0101

AC:

1232

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0149

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:22Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 10, 2012	Ala213Val in exon 2 of DES: This variant has been reported by several studies an d was initially thought to be disease causing (Goldfarb 2004, Bar 2004, Kostarev a 2006). However, it has been identified in 0.4% (8/2000) of chromosomes from a broad, though clinically and racially unspecified population (dbSNP rs41272699) and in 1.5% (102/7020) of European American chromosomes and 0.4% (14/3738) of Af rican American chromosomes by the NHBLI Exome sequencing project in a clinical c ohort that included individuals with heart disease (http://evs.gs.washington.edu /EVS). With a frequency this high the variant is considered to be benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 04, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 03, 2018	Variant summary: DES c.638C>T (p.Ala213Val) results in a non-conservative amino acid change located in the Intermediate filament, rod domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0094 in 278984 control chromosomes in the gnomAD database, including 28 homozygotes. The observed variant frequency is approximately 375 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.638C>T has been reported in the literature in individuals affected with Cardiomyopathy as well as in controls. In one study, the variant failed to segregate with disease in a family, being found in 4 healthy individuals and was absent in 1 affected individual (Taylor_2007). In functional studies, cells expressing the variant showed normal complete filamentous network (Bar_2005, Goudeau_2006). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:5Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 33232181, 32105824, 22215463, 25736269, 17325244, 23861362, 20474083, 27618136, 22260945, 16865695, 21842594, 25617006, 23168288) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Desmin-related myofibrillar myopathy

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	European (non-Finnish) population allele frequency is 1.5% (rs41272699, 1,953/129,178 alleles, 20 homozygotes in gnomAD v2.1). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -
Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Myofibrillar myopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Aug 16, 2016

- -

Congenital diaphragmatic hernia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Mar 03, 2015

It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. -

Myofibrillar Myopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated cardiomyopathy 1I

Benign:1

Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Neurogenic scapuloperoneal syndrome, Kaeser type

Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 15, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2015

This alteration is classified as 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

Benign

0.26

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

Eigen

Benign

0.17

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.0041

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.36

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0080

Polyphen

0.90

Vest4

0.59

MPC

0.011

ClinPred

0.017

GERP RS

3.7

Varity_R

0.40

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.053

dbscSNV1_RF

Benign

0.30

SpliceAI score (max)

0.030

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