2-219420057-C-T

Variant names:

• chr2-219420057-C-T
• rs12991025
• NM_001927.4:c.579-38C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001927.4(DES):​c.579-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 1,612,128 control chromosomes in the GnomAD database, including 323,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.51 (23854 hom., cov: 32)
  • Exomes 𝑓: 0.63 (300142 hom.)
• Consequence: DES NM_001927.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.356
• Publications: 9 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-219420057-C-T is Benign according to our data. Variant chr2-219420057-C-T is described in ClinVar as [Benign]. Clinvar id is 258491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.579-38C>T		intron_variant	Intron 1 of 8	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.579-38C>T		intron_variant	Intron 1 of 8	1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.15C>T		non_coding_transcript_exon_variant	Exon 1 of 8	4
DES	ENST00000492726.1	n.-65C>T		upstream_gene_variant		4
DES	ENST00000683013.1	n.-167C>T		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78131 AN: 151906 Hom.: 23852 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.529

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.525

GnomAD2 exomes AF: 0.627 AC: 157680 AN: 251340 AF XY: 0.634

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.560

Gnomad EAS exome AF: 0.809

Gnomad FIN exome AF: 0.718

Gnomad NFE exome AF: 0.631

Gnomad OTH exome AF: 0.613

GnomAD4 exome AF: 0.635 AC: 927141 AN: 1460104 Hom.: 300142 Cov.: 35 AF XY: 0.637 AC XY: 462738 AN XY: 726482

African (AFR) AF: 0.146 AC: 4895 AN: 33424

American (AMR) AF: 0.656 AC: 29340 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 14729 AN: 26128

East Asian (EAS) AF: 0.816 AC: 32404 AN: 39692

South Asian (SAS) AF: 0.677 AC: 58339 AN: 86232

European-Finnish (FIN) AF: 0.721 AC: 38505 AN: 53392

Middle Eastern (MID) AF: 0.527 AC: 3014 AN: 5720

European-Non Finnish (NFE) AF: 0.639 AC: 709219 AN: 1110464

Other (OTH) AF: 0.608 AC: 36696 AN: 60336

GnomAD4 genome AF: 0.514 AC: 78127 AN: 152024 Hom.: 23854 Cov.: 32 AF XY: 0.521 AC XY: 38719 AN XY: 74304

African (AFR) AF: 0.165 AC: 6851 AN: 41454

American (AMR) AF: 0.586 AC: 8954 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1953 AN: 3470

East Asian (EAS) AF: 0.814 AC: 4191 AN: 5148

South Asian (SAS) AF: 0.678 AC: 3270 AN: 4820

European-Finnish (FIN) AF: 0.732 AC: 7746 AN: 10584

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.639 AC: 43403 AN: 67958

Other (OTH) AF: 0.518 AC: 1096 AN: 2114

Alfa AF: 0.572 Hom.: 8650

Bravo AF: 0.488

Asia WGS AF: 0.672 AC: 2337 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Desmin-related myofibrillar myopathy Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1I Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurogenic scapuloperoneal syndrome, Kaeser type Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.6
DANN	Benign	0.71
PhyloP100		-0.36
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12991025; hg19: chr2-220284779; COSMIC: COSV64660440; COSMIC: COSV64660440;