rs41272701

Positions:

• chr2-219420460-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000373960.4(DES):​c.736-35C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 1,613,716 control chromosomes in the GnomAD database, including 1,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (126 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1486 hom.)
• Consequence: DES ENST00000373960.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0820

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-219420460-C-A is Benign according to our data. Variant chr2-219420460-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 258492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219420460-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0336 (5115/152122) while in subpopulation NFE AF= 0.0498 (3385/67982). AF 95% confidence interval is 0.0484. There are 126 homozygotes in gnomad4. There are 2437 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 126 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.736-35C>A		intron_variant		ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.736-35C>A		intron_variant		1	NM_001927.4	ENSP00000363071	P1
DES	ENST00000477226.6	n.210-35C>A		intron_variant, non_coding_transcript_variant		4
DES	ENST00000492726.1	n.131-35C>A		intron_variant, non_coding_transcript_variant		4
DES	ENST00000683013.1	n.124-35C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5115 AN: 152004 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.00829

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0540

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0355 AC: 8877 AN: 250162 Hom.: 202 AF XY: 0.0362 AC XY: 4896 AN XY: 135308

Gnomad AFR exome AF: 0.00700

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0612

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0230

Gnomad FIN exome AF: 0.0495

Gnomad NFE exome AF: 0.0495

Gnomad OTH exome AF: 0.0373

GnomAD4 exome AF: 0.0428 AC: 62566 AN: 1461594 Hom.: 1486 Cov.: 36 AF XY: 0.0426 AC XY: 30958 AN XY: 727084

Gnomad4 AFR exome AF: 0.00771

Gnomad4 AMR exome AF: 0.0177

Gnomad4 ASJ exome AF: 0.0627

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0239

Gnomad4 FIN exome AF: 0.0495

Gnomad4 NFE exome AF: 0.0473

Gnomad4 OTH exome AF: 0.0380

GnomAD4 genome AF: 0.0336 AC: 5115 AN: 152122 Hom.: 126 Cov.: 32 AF XY: 0.0328 AC XY: 2437 AN XY: 74348

Gnomad4 AFR AF: 0.00826

Gnomad4 AMR AF: 0.0210

Gnomad4 ASJ AF: 0.0579

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0208

Gnomad4 FIN AF: 0.0540

Gnomad4 NFE AF: 0.0498

Gnomad4 OTH AF: 0.0266

Alfa AF: 0.0424 Hom.: 23

Bravo AF: 0.0304

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.2
DANN	Benign	0.84

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: rs41272701; hg19: chr2-220285182;