rs397516699

Variant names:

• chr2-219420658-TGG-T
• rs397516699
• NM_001927.4:c.897+4_897+5delGG

Your query was ambiguous. Multiple possible variants found:

• chr2-219420658-TGG-T
• chr2-219420658-TGG-TG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001927.4(DES):​c.897+4_897+5delGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,966 control chromosomes in the GnomAD database, including 39 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (39 hom.)
• Consequence: DES NM_001927.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.421
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1I

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• myofibrillar myopathy 1

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• atrioventricular block

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neurogenic scapuloperoneal syndrome, Kaeser type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-219420658-TGG-T is Benign according to our data. Variant chr2-219420658-TGG-T is described in ClinVar as [Likely_benign]. Clinvar id is 44273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000473 (72/152142) while in subpopulation SAS AF = 0.0133 (64/4814). AF 95% confidence interval is 0.0107. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 39 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.897+4_897+5delGG		splice_region_variant, intron_variant	Intron 4 of 8	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.897+3_897+4delGG		splice_region_variant, intron_variant	Intron 4 of 8	1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.371+3_371+4delGG		splice_region_variant, intron_variant	Intron 3 of 7	4
DES	ENST00000492726.1	n.292+3_292+4delGG		splice_region_variant, intron_variant	Intron 3 of 5	4
DES	ENST00000683013.1	n.285+3_285+4delGG		splice_region_variant, intron_variant	Intron 2 of 6

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152024 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00210 AC: 528 AN: 251216 AF XY: 0.00297

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00106 AC: 1553 AN: 1461824 Hom.: 39 AF XY: 0.00160 AC XY: 1162 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0161 AC: 1393 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.0000585 AC: 65 AN: 1112010

Other (OTH) AF: 0.000778 AC: 47 AN: 60396

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.000659 AC XY: 49 AN XY: 74356

African (AFR) AF: 0.0000482 AC: 2 AN: 41518

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.000113

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1;BP5 -

Sep 01, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.897+4_897+5delGG in intron 4 of DES: This variant is not expected to have clin ical significance because it has been identified in 1.6% (260/16508) of South As ian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs397516699). -

Feb 13, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Desmin-related myofibrillar myopathy Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DES: BP4, BS1, BS2 -

Oct 24, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33250842, 27535533, 20474083) -

Dilated cardiomyopathy 1I Benign:1

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.897+4_897+5delGG variant in DES has been identified in an individual with dilated cardiomyopathy (PMID: 20474083), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant dilated cardiomyopathy. -

Myofibrillar Myopathy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Jul 30, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Scapuloperoneal weakness Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DES-related disorder Benign:1

Jan 30, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Mar 13, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.42
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516699; hg19: chr2-220285380;