rs139754493

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP3BP4_ModerateBS1_SupportingBS2

The NM_001130987.2(DYSF):​c.2020A>G​(p.Lys674Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000699 in 1,581,850 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00072 ( 4 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

9
8
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:2

Conservation

PhyloP100: 9.31

Publications

8 publications found
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]
DYSF Gene-Disease associations (from GenCC):
  • autosomal recessive limb-girdle muscular dystrophy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • neuromuscular disease caused by qualitative or quantitative defects of dysferlin
    Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
  • autosomal recessive limb-girdle muscular dystrophy type 2B
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
  • distal myopathy with anterior tibial onset
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • congenital myopathy, Paradas type
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Miyoshi myopathy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.15630594).
BS1
Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000715 (1025/1432870) while in subpopulation SAS AF = 0.00185 (159/85920). AF 95% confidence interval is 0.00162. There are 4 homozygotes in GnomAdExome4. There are 541 alleles in the male GnomAdExome4 subpopulation. Median coverage is 39. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYSFNM_001130987.2 linkc.2020A>G p.Lys674Glu missense_variant Exon 21 of 56 ENST00000410020.8 NP_001124459.1 O75923-13
DYSFNM_003494.4 linkc.1966A>G p.Lys656Glu missense_variant Exon 21 of 55 ENST00000258104.8 NP_003485.1 O75923-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DYSFENST00000410020.8 linkc.2020A>G p.Lys674Glu missense_variant Exon 21 of 56 1 NM_001130987.2 ENSP00000386881.3 O75923-13
DYSFENST00000258104.8 linkc.1966A>G p.Lys656Glu missense_variant Exon 21 of 55 1 NM_003494.4 ENSP00000258104.3 O75923-1

Frequencies

GnomAD3 genomes
AF:
0.000537
AC:
80
AN:
148878
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000247
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000135
Gnomad ASJ
AF:
0.00406
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00198
Gnomad FIN
AF:
0.00129
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000594
Gnomad OTH
AF:
0.000487
GnomAD2 exomes
AF:
0.000816
AC:
205
AN:
251164
AF XY:
0.00103
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000289
Gnomad ASJ exome
AF:
0.00308
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00116
Gnomad NFE exome
AF:
0.000687
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000715
AC:
1025
AN:
1432870
Hom.:
4
Cov.:
39
AF XY:
0.000759
AC XY:
541
AN XY:
712822
show subpopulations
African (AFR)
AF:
0.0000612
AC:
2
AN:
32676
American (AMR)
AF:
0.000274
AC:
12
AN:
43832
Ashkenazi Jewish (ASJ)
AF:
0.00300
AC:
75
AN:
25016
East Asian (EAS)
AF:
0.0000269
AC:
1
AN:
37126
South Asian (SAS)
AF:
0.00185
AC:
159
AN:
85920
European-Finnish (FIN)
AF:
0.000981
AC:
50
AN:
50966
Middle Eastern (MID)
AF:
0.00179
AC:
10
AN:
5596
European-Non Finnish (NFE)
AF:
0.000616
AC:
673
AN:
1093284
Other (OTH)
AF:
0.000736
AC:
43
AN:
58454
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
61
122
182
243
304
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
28
56
84
112
140
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000544
AC:
81
AN:
148980
Hom.:
0
Cov.:
32
AF XY:
0.000661
AC XY:
48
AN XY:
72566
show subpopulations
African (AFR)
AF:
0.0000246
AC:
1
AN:
40646
American (AMR)
AF:
0.000134
AC:
2
AN:
14872
Ashkenazi Jewish (ASJ)
AF:
0.00406
AC:
14
AN:
3450
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4780
South Asian (SAS)
AF:
0.00220
AC:
10
AN:
4548
European-Finnish (FIN)
AF:
0.00129
AC:
13
AN:
10046
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
284
European-Non Finnish (NFE)
AF:
0.000594
AC:
40
AN:
67378
Other (OTH)
AF:
0.000482
AC:
1
AN:
2074
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
4
8
12
16
20
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000691
Hom.:
0
Bravo
AF:
0.000404
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000848
AC:
103
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000872
EpiControl
AF:
0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4Benign:1
Dec 06, 2018
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in published literature (Pavoni et al., 2011) as 1966 A>G; K656Q,due to the use of alternate nomenclature, in individual with Miyoshi myopathy who also harbored the c.2200_2205delinsT; the phase of these variants is unknown; This variant is associated with the following publications: (PMID: 22046204, 21522182) -

Sep 19, 2022
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 03, 2021
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 04, 2015
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 25, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Limb-girdle muscular dystrophy, recessive Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Distal myopathy with anterior tibial onset Uncertain:1
Jul 14, 2021
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

DYSF-related disorder Uncertain:1
Mar 21, 2023
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The DYSF c.1966A>G variant is predicted to result in the amino acid substitution p.Lys656Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.31% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including 1 homozygote (http://gnomad.broadinstitute.org/variant/2-71780972-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
Jul 14, 2021
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Miyoshi muscular dystrophy 1 Uncertain:1
Jul 14, 2021
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Miyoshi myopathy Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.096
D
BayesDel_noAF
Pathogenic
0.36
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
.;.;.;.;D;.;.;.;.;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.56
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
0.52
D
MetaRNN
Benign
0.16
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.79
D
MutationAssessor
Pathogenic
3.8
.;.;H;.;H;.;.;.;.;.;.
PhyloP100
9.3
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.6
D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.99
D;D;D;P;P;P;P;D;P;D;D
Vest4
0.91
MVP
0.86
MPC
0.74
ClinPred
0.20
T
GERP RS
3.7
Varity_R
0.66
gMVP
0.89
Mutation Taster
=100/0
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs139754493; hg19: chr2-71780972; COSMIC: COSV99064700; API