2-219418555-T-C

Position:

• chr2-219418555-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001927.4(DES):​c.93T>C​(p.Ser31Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,604,920 control chromosomes in the GnomAD database, including 758,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (61082 hom., cov: 33)
  • Exomes 𝑓: 0.98 (697176 hom.)
• Consequence: DES NM_001927.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 1.70

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 2-219418555-T-C is Benign according to our data. Variant chr2-219418555-T-C is described in ClinVar as [Benign]. Clinvar id is 36003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418555-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.93T>C	p.Ser31Ser	synonymous_variant	1/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.93T>C	p.Ser31Ser	synonymous_variant	1/9	1	NM_001927.4	ENSP00000363071.3

Frequencies

GnomAD3 genomes AF: 0.881 AC: 133900 AN: 152060 Hom.: 61069 Cov.: 33

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.949

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.976

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.907

GnomAD3 exomes AF: 0.964 AC: 219435 AN: 227618 Hom.: 106697 AF XY: 0.969 AC XY: 122256 AN XY: 126124

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.976

Gnomad ASJ exome AF: 0.989

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.974

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.988

Gnomad OTH exome AF: 0.976

GnomAD4 exome AF: 0.978 AC: 1420620 AN: 1452750 Hom.: 697176 Cov.: 74 AF XY: 0.979 AC XY: 707161 AN XY: 722376

Gnomad4 AFR exome AF: 0.601

Gnomad4 AMR exome AF: 0.973

Gnomad4 ASJ exome AF: 0.988

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.974

Gnomad4 FIN exome AF: 0.997

Gnomad4 NFE exome AF: 0.989

Gnomad4 OTH exome AF: 0.962

GnomAD4 genome AF: 0.880 AC: 133951 AN: 152170 Hom.: 61082 Cov.: 33 AF XY: 0.885 AC XY: 65811 AN XY: 74400

Gnomad4 AFR AF: 0.609

Gnomad4 AMR AF: 0.949

Gnomad4 ASJ AF: 0.986

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.976

Gnomad4 FIN AF: 0.997

Gnomad4 NFE AF: 0.988

Gnomad4 OTH AF: 0.908

Alfa AF: 0.969 Hom.: 18405

Bravo AF: 0.867

Asia WGS AF: 0.962 AC: 3335 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

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	-	- -
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	Jul 20, 2011	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2016	- -

Desmin-related myofibrillar myopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dilated cardiomyopathy 1I Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neurogenic scapuloperoneal syndrome, Kaeser type Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

Myofibrillar Myopathy, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.83

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: rs2017800; hg19: chr2-220283277; COSMIC: COSV64660277; COSMIC: COSV64660277;