rs41272701

Variant names:

• chr2-219420460-C-A
• rs41272701
• NM_001927.4:c.736-35C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-219420460-C-A
• chr2-219420460-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001927.4(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 NM_001927.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0820
• Publications: 5 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: 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 Benign/Likely_benign. ClinVar VariationId is 258492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 126 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.736-35C>A		intron_variant	Intron 3 of 8	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.736-35C>A		intron_variant	Intron 3 of 8	1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.210-35C>A		intron_variant	Intron 2 of 7	4
DES	ENST00000492726.1	n.131-35C>A		intron_variant	Intron 2 of 5	4
DES	ENST00000683013.1	n.124-35C>A		intron_variant	Intron 1 of 6

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

GnomAD2 exomes AF: 0.0355 AC: 8877 AN: 250162 AF XY: 0.0362

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 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

African (AFR) AF: 0.00771 AC: 258 AN: 33478

American (AMR) AF: 0.0177 AC: 790 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1638 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0239 AC: 2065 AN: 86228

European-Finnish (FIN) AF: 0.0495 AC: 2638 AN: 53334

Middle Eastern (MID) AF: 0.0505 AC: 291 AN: 5762

European-Non Finnish (NFE) AF: 0.0473 AC: 52590 AN: 1111870

Other (OTH) AF: 0.0380 AC: 2294 AN: 60392

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

African (AFR) AF: 0.00826 AC: 343 AN: 41506

American (AMR) AF: 0.0210 AC: 321 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 201 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.0208 AC: 100 AN: 4816

European-Finnish (FIN) AF: 0.0540 AC: 572 AN: 10594

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0498 AC: 3385 AN: 67982

Other (OTH) AF: 0.0266 AC: 56 AN: 2108

Alfa AF: 0.0429 Hom.: 52

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jun 15, 2018

GeneDx

Significance: Likely 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.2
DANN	Benign	0.84
PhyloP100		-0.082
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: rs41272701; hg19: chr2-220285182;