chr2-219418537-A-G

Position:

• chr2-219418537-A-G

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.75A>G​(p.Pro25Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,602,894 control chromosomes in the GnomAD database, including 760,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62755 hom., cov: 34)
  • Exomes 𝑓: 0.98 (698137 hom.)
• Consequence: DES NM_001927.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.0430

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=-0.84).
• BP6: Variant 2-219418537-A-G is Benign according to our data. Variant chr2-219418537-A-G is described in ClinVar as [Benign]. Clinvar id is 36002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219418537-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.043 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.75A>G	p.Pro25Pro	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.75A>G	p.Pro25Pro	synonymous_variant	1/9	1	NM_001927.4	ENSP00000363071.3

Frequencies

GnomAD3 genomes AF: 0.897 AC: 136433 AN: 152046 Hom.: 62740 Cov.: 34

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.956

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.976

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.918

GnomAD3 exomes AF: 0.968 AC: 217879 AN: 225084 Hom.: 106161 AF XY: 0.972 AC XY: 121604 AN XY: 125074

Gnomad AFR exome AF: 0.643

Gnomad AMR exome AF: 0.979

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: 0.989

Gnomad OTH exome AF: 0.978

GnomAD4 exome AF: 0.980 AC: 1421249 AN: 1450738 Hom.: 698137 Cov.: 71 AF XY: 0.981 AC XY: 707505 AN XY: 721554

Gnomad4 AFR exome AF: 0.651

Gnomad4 AMR exome AF: 0.977

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: 0.966

GnomAD4 genome AF: 0.897 AC: 136489 AN: 152156 Hom.: 62755 Cov.: 34 AF XY: 0.901 AC XY: 66986 AN XY: 74386

Gnomad4 AFR AF: 0.667

Gnomad4 AMR AF: 0.956

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: 0.919

Alfa AF: 0.973 Hom.: 17041

Bravo AF: 0.885

Asia WGS AF: 0.965 AC: 3348 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 12, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	-	- -

Desmin-related myofibrillar myopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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 13, 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 13, 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	-0.84
CADD	Benign	12
DANN	Benign	0.64

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: rs1318299; hg19: chr2-220283259; COSMIC: COSV64659755; COSMIC: COSV64659755;