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rs727503910

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001130987.2(DYSF):c.2844G>C(p.Trp948Cys) variant causes a missense 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

DYSF
NM_001130987.2 missense

Scores

10
6
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 7.93
Variant links:
Genes affected
DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 2-71568318-G-C is Pathogenic according to our data. Variant chr2-71568318-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167021.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, Pathogenic=2}. Variant chr2-71568318-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DYSFNM_001130987.2 linkuse as main transcriptc.2844G>C p.Trp948Cys missense_variant 26/56 ENST00000410020.8
DYSFNM_003494.4 linkuse as main transcriptc.2790G>C p.Trp930Cys missense_variant 26/55 ENST00000258104.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DYSFENST00000410020.8 linkuse as main transcriptc.2844G>C p.Trp948Cys missense_variant 26/561 NM_001130987.2 A1O75923-13
DYSFENST00000258104.8 linkuse as main transcriptc.2790G>C p.Trp930Cys missense_variant 26/551 NM_003494.4 A1O75923-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Qualitative or quantitative defects of dysferlin Pathogenic:2
Likely pathogenic, criteria provided, single submitterresearchJain FoundationMar 13, 2023This variant is absent from gnomAD v2.1.1. This variant has been reported in individuals with a clinical phenotype consistent with dysferlinopathy, associated with disease range dysferlin protein levels, and found in the heterozygous state in conjuction with the pathogeic or likely pathogenic DYSF variants, c.2643+1G>A, c.4024C>T, or c.3832C>T (PMID: 36983702, 18853459). This variant has also been reported to cause reduced dysferlin protein expression and no plasma membrane localization via an in vitro assay (PMID: 35028538). Both the REVEL (0.867) and CADD (25.7) scores support a deleterious effect. The ACMG classification criteria applied are: PM2 moderate, PM3 moderate, PP3, PP4 moderate, and PS3 supporting. Based on the above data, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 17, 2023This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 930 of the DYSF protein (p.Trp930Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 18853459, 33610434). ClinVar contains an entry for this variant (Variation ID: 167021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 18, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 05, 2016- -
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 09, 2023- -
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylAug 03, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
Cadd
Uncertain
25
Dann
Uncertain
0.99
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.64
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-12
D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.015
D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D;D;D;D;D;D
Vest4
0.98
MutPred
0.92
.;.;Loss of sheet (P = 0.0084);.;Loss of sheet (P = 0.0084);.;.;.;.;.;.;
MVP
0.93
MPC
0.82
ClinPred
1.0
D
GERP RS
4.1
Varity_R
0.93
gMVP
0.94

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: rs727503910; hg19: chr2-71795448; API