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GeneBe

rs145272777

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001130987.2(DYSF):c.5333C>A(p.Pro1778Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4

Conservation

PhyloP100: -0.0560
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.009371072).
BP6
Variant 2-71667391-C-A is Benign according to our data. Variant chr2-71667391-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285686.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=3}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DYSFNM_001130987.2 linkuse as main transcriptc.5333C>A p.Pro1778Gln missense_variant 48/56 ENST00000410020.8
DYSFNM_003494.4 linkuse as main transcriptc.5216C>A p.Pro1739Gln missense_variant 47/55 ENST00000258104.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DYSFENST00000410020.8 linkuse as main transcriptc.5333C>A p.Pro1778Gln missense_variant 48/561 NM_001130987.2 A1O75923-13
DYSFENST00000258104.8 linkuse as main transcriptc.5216C>A p.Pro1739Gln missense_variant 47/551 NM_003494.4 A1O75923-1

Frequencies

GnomAD3 genomes
AF:
0.000355
AC:
54
AN:
152166
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00663
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000323
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000562
AC:
141
AN:
250878
Hom.:
0
AF XY:
0.000604
AC XY:
82
AN XY:
135742
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000289
Gnomad ASJ exome
AF:
0.00576
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000457
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000485
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000350
AC:
511
AN:
1461832
Hom.:
0
Cov.:
32
AF XY:
0.000378
AC XY:
275
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00524
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000591
Gnomad4 FIN exome
AF:
0.000112
Gnomad4 NFE exome
AF:
0.000219
Gnomad4 OTH exome
AF:
0.000762
GnomAD4 genome
AF:
0.000355
AC:
54
AN:
152284
Hom.:
0
Cov.:
33
AF XY:
0.000309
AC XY:
23
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00663
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000323
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000653
Hom.:
1
Bravo
AF:
0.000382
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000519
AC:
63
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000927
EpiControl
AF:
0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2018- -
Likely benign, criteria provided, single submitterclinical testingGeneDxSep 09, 2020This variant is associated with the following publications: (PMID: 30564623, 27647186) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 04, 2017- -
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:2Benign:1
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Jan 06, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylJan 10, 2017- -
Miyoshi muscular dystrophy 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 28, 2019This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 20, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaFeb 13, 2018The DYSF gene is the only gene in which variants are known to cause dysferlinopathy. The DYSF c.5216C>A (p.Pro1739Gln) missense variant has been reported in one study in which it is found in two siblings from a family with a history of dysferlinopathy. The variant was found in a compound heterozygous state with a deletion in one sibling and in a heterozygous state in the other (Jin et al. 2016). Both siblings were found to be negative for dysferlin expression using immunohistochemical analysis of muscle tissue (Jin et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.005924 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Pro1739Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Distal myopathy with anterior tibial onset Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
DYSF-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 06, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.31
Cadd
Benign
17
Dann
Benign
0.86
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.85
D;T;T;D;D;D;D;T;T;T;D
M_CAP
Benign
0.067
D
MetaRNN
Benign
0.0094
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.69
T
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-2.1
N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.14
Sift
Benign
0.066
T;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.71
T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0010
B;B;B;B;B;B;B;B;B;B;B
Vest4
0.40
MVP
0.70
MPC
0.14
ClinPred
0.013
T
GERP RS
3.3
Varity_R
0.047
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs145272777; hg19: chr2-71894521; API