2-219418432-T-TGCGCCCGCCAGCC

Variant names:

• chr2-219418432-T-TGCGCCCGCCAGCC
• rs794728983
• NM_001927.4:c.-30_-18dupGCGCCCGCCAGCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001927.4(DES):​c.-30_-18dupGCGCCCGCCAGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 1,552,212 control chromosomes in the GnomAD database, including 173 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (101 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (72 hom.)
• Consequence: DES NM_001927.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.502

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 -16 ACMG points.

• BP6: Variant 2-219418432-T-TGCGCCCGCCAGCC is Benign according to our data. Variant chr2-219418432-T-TGCGCCCGCCAGCC is described in ClinVar as [Benign]. Clinvar id is 201699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.-30_-18dupGCGCCCGCCAGCC		5_prime_UTR_variant	Exon 1 of 9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960	c.-30_-18dupGCGCCCGCCAGCC		5_prime_UTR_variant	Exon 1 of 9	1	NM_001927.4	ENSP00000363071.3

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2771 AN: 152006 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.0631

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00160 AC: 2237 AN: 1400096 Hom.: 72 Cov.: 29 AF XY: 0.00134 AC XY: 930 AN XY: 694576

Gnomad4 AFR exome AF: 0.0607

Gnomad4 AMR exome AF: 0.00234

Gnomad4 ASJ exome AF: 0.0000404

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000149

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000825

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.0183 AC: 2779 AN: 152116 Hom.: 101 Cov.: 32 AF XY: 0.0176 AC XY: 1309 AN XY: 74382

Gnomad4 AFR AF: 0.0631

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00993 Hom.: 3

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, flagged submission	clinical testing	GeneDx	Jun 04, 2014	The variant is found in DCM,DCM-CRDM panel(s). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2020	Variant summary: DES c.-30_-18dup13 is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0011 in 165222 control chromosomes, predominantly at a frequency of 0.024 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 768-fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.3330+5G>C; Internal testing), providing supporting evidence for a benign role. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2015	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728983; hg19: chr2-220283154;