2-219420347-G-A

Position:

• chr2-219420347-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_001927.4(DES):​c.735+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DES NM_001927.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.86

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06723284 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-219420347-G-A is Pathogenic according to our data. Variant chr2-219420347-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219420347-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.735+1G>A		splice_donor_variant		ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.735+1G>A		splice_donor_variant		1	NM_001927.4	P1
DES	ENST00000477226.6	n.209+1G>A		splice_donor_variant, non_coding_transcript_variant		4
DES	ENST00000492726.1	n.130+1G>A		splice_donor_variant, non_coding_transcript_variant		4
DES	ENST00000683013.1	n.123+1G>A		splice_donor_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desmin-related myofibrillar myopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 20, 2019	Disruption of this splice site has been observed in several individuals affected with clinical features of autosomal dominant desminopathy (PMID: 30614851, 28703267). ClinVar contains an entry for this variant (Variation ID: 44268). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the DES gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 29034897). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DES are known to be pathogenic (PMID: 23575897). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 22, 2017	The c.735+1G>A variant in DES has been reported in at least 2 individuals with d esminopathy (Shatunov et al., unpublished data; reviewed by Goldfarb 2004, Gudko va 2013, LMM data), and was absent from large population studies. This variant o ccurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Ad ditional variants affecting splicing of this exon have been reported in individu als with desminopathy including a different variant at the same position (c.7351 +G>C LMM data: variant occurred de novo) and c.735+3A>G (identified in 6 individ uals with desminopathy and segregated in 9 individuals from 2 families: Park 200 0, Dalakas 2000, Wahni 2012, Greenberg 2012, McDonald 2012, Gudkova 2013, LMM un published data). In summary, although additional studies are required to fully e stablish its clinical significance, the c.735+1G>A variant is likely pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -13
DS_DL_spliceai		0.94		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516698; hg19: chr2-220285069;