rs41272699

chr2-219420154-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A213T) has been classified as Uncertain significance.

• 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:1 U:1 B:22 O:1
• Conservation: PhyloP100: 1.51

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 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: {Benign=10, Likely_benign=6, 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 GnomAd at 12 SD gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.638C>T	p.Ala213Val	missense_variant, splice_region_variant	2/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.112C>T		splice_region_variant, non_coding_transcript_exon_variant	1/8	4
DES	ENST00000492726.1	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.: 12 Cov.: 32

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.: 24 AF XY: 0.00996 AC XY: 1354 AN XY: 135908

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.: 36 AF XY: 0.0142 AC XY: 10361 AN XY: 727236

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.: 12 Cov.: 32 AF XY: 0.00890 AC XY: 663 AN XY: 74492

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.: 36

Bravo AF: 0.00963

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0137 AC: 118

ExAC AF: 0.0101 AC: 1232

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0149

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 01, 2017	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 04, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:5 Other: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) -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Desmin-related myofibrillar myopathy Benign:3

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. -
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 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.0041	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.90	P
Vest4		0.59
MPC		0.011
ClinPred		0.017	T
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

Other links and lift over

dbSNP: rs41272699; hg19: chr2-220284876; COSMIC: COSV99059323; COSMIC: COSV99059323;