rs776452710

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The ENST00000410020.8(DYSF):ā€‹c.5210C>Gā€‹(p.Pro1737Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1737P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

DYSF
ENST00000410020.8 missense

Scores

16
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.68
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
Variant 2-71665197-C-G is Pathogenic according to our data. Variant chr2-71665197-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567124.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYSFNM_001130987.2 linkuse as main transcriptc.5210C>G p.Pro1737Arg missense_variant 47/56 ENST00000410020.8 NP_001124459.1
DYSFNM_003494.4 linkuse as main transcriptc.5093C>G p.Pro1698Arg missense_variant 46/55 ENST00000258104.8 NP_003485.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DYSFENST00000410020.8 linkuse as main transcriptc.5210C>G p.Pro1737Arg missense_variant 47/561 NM_001130987.2 ENSP00000386881 A1O75923-13
DYSFENST00000258104.8 linkuse as main transcriptc.5093C>G p.Pro1698Arg missense_variant 46/551 NM_003494.4 ENSP00000258104 A1O75923-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251222
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461694
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

Qualitative or quantitative defects of dysferlin Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 22, 2023This variant is present in population databases (rs776452710, gnomAD 0.003%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 567124). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (LGMD) (Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1698 of the DYSF protein (p.Pro1698Arg). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 13, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.46
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
.;.;.;.;D;.;.;.;.;.;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.4
.;.;.;.;M;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-7.9
D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
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
0.95
MutPred
0.64
.;.;.;.;Gain of MoRF binding (P = 0.0064);.;.;.;.;.;.;
MVP
0.97
MPC
0.66
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.85
gMVP
0.87

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: rs776452710; hg19: chr2-71892327; API