2-219425727-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1

The ENST00000373960.4(DES):​c.1353C>T​(p.Ile451=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,602,978 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

DES
ENST00000373960.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -2.88
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 2-219425727-C-T is Benign according to our data. Variant chr2-219425727-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226559.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=1}. Variant chr2-219425727-C-T is described in Lovd as [Benign]. Variant chr2-219425727-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.88 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00025 (38/152044) while in subpopulation EAS AF= 0.00601 (31/5156). AF 95% confidence interval is 0.00435. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DESNM_001927.4 linkuse as main transcriptc.1353C>T p.Ile451= synonymous_variant 8/9 ENST00000373960.4 NP_001918.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DESENST00000373960.4 linkuse as main transcriptc.1353C>T p.Ile451= synonymous_variant 8/91 NM_001927.4 ENSP00000363071 P1
ENST00000431827.1 linkuse as main transcriptn.104+354G>A intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.000250
AC:
38
AN:
151926
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00600
Gnomad SAS
AF:
0.000417
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000564
AC:
131
AN:
232466
Hom.:
1
AF XY:
0.000528
AC XY:
66
AN XY:
125040
show subpopulations
Gnomad AFR exome
AF:
0.000138
Gnomad AMR exome
AF:
0.0000309
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00717
Gnomad SAS exome
AF:
0.000108
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000955
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000128
AC:
185
AN:
1450934
Hom.:
1
Cov.:
31
AF XY:
0.000129
AC XY:
93
AN XY:
720560
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.0000233
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00338
Gnomad4 SAS exome
AF:
0.000191
Gnomad4 FIN exome
AF:
0.0000189
Gnomad4 NFE exome
AF:
0.00000361
Gnomad4 OTH exome
AF:
0.000483
GnomAD4 genome
AF:
0.000250
AC:
38
AN:
152044
Hom.:
0
Cov.:
32
AF XY:
0.000256
AC XY:
19
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00601
Gnomad4 SAS
AF:
0.000417
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000947
Bravo
AF:
0.000193
Asia WGS
AF:
0.00289
AC:
10
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 10, 2015- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 01, 2015p.Ile451Ile in exon 8 of DES:This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 1.1% (43/3920) of Eas t Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs121913002). -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Desmin-related myofibrillar myopathy Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024- -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMay 03, 2021- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 10, 2017This alteration is classified as likely 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
-0.52
CADD
Benign
2.5
DANN
Benign
0.85

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913002; hg19: chr2-220290449; COSMIC: COSV64660284; COSMIC: COSV64660284; API