chr2-71598577-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.3534C>T p.(Ile1178=) variant in DYSF, which is also known as NM_001130987.2: c.3588C>T (p.Ile1196=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). The filtering allele frequency for this variant is 0.008874 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 10642/1180038 European (non-Finnish) chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). This variant was detected in a heterozygous state in one individual with suspected LGMD and absent dysferlin expression by blood monocyte assay. No second variant in DYSF was identified, and this individual also had two variants in DNAJB6 (PMID:25493284, 36983702). The SpliceAI prediction score for this variant is 0.27, which is greater than the VCEP threshold of <0.05 (BP4 not met). However, RNASeq data showed this variant does not affect splicing (PMID:36983702). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/19/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA152665/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.0061 ( 6 hom., cov: 33)
Exomes 𝑓: 0.0079 ( 53 hom. )

Consequence

DYSF
NM_001130987.2 synonymous

Scores

2

Clinical Significance

Benign reviewed by expert panel U:3B:11

Conservation

PhyloP100: -0.617

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: Benign. The variant received -8 ACMG points.

BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYSFNM_001130987.2 linkc.3588C>T p.Ile1196Ile synonymous_variant Exon 33 of 56 ENST00000410020.8 NP_001124459.1 O75923-13
DYSFNM_003494.4 linkc.3534C>T p.Ile1178Ile synonymous_variant Exon 33 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.3588C>T p.Ile1196Ile synonymous_variant Exon 33 of 56 1 NM_001130987.2 ENSP00000386881.3 O75923-13
DYSFENST00000258104.8 linkc.3534C>T p.Ile1178Ile synonymous_variant Exon 33 of 55 1 NM_003494.4 ENSP00000258104.3 O75923-1

Frequencies

GnomAD3 genomes
AF:
0.00614
AC:
934
AN:
152218
Hom.:
6
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00169
Gnomad AMI
AF:
0.0340
Gnomad AMR
AF:
0.00196
Gnomad ASJ
AF:
0.0156
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.00828
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00948
Gnomad OTH
AF:
0.00573
GnomAD2 exomes
AF:
0.00666
AC:
1673
AN:
251142
AF XY:
0.00678
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.00156
Gnomad ASJ exome
AF:
0.0130
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00827
Gnomad NFE exome
AF:
0.0105
Gnomad OTH exome
AF:
0.00750
GnomAD4 exome
AF:
0.00787
AC:
11498
AN:
1461862
Hom.:
53
Cov.:
32
AF XY:
0.00790
AC XY:
5747
AN XY:
727226
show subpopulations
African (AFR)
AF:
0.00128
AC:
43
AN:
33480
American (AMR)
AF:
0.00186
AC:
83
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.0115
AC:
300
AN:
26136
East Asian (EAS)
AF:
0.000101
AC:
4
AN:
39700
South Asian (SAS)
AF:
0.00179
AC:
154
AN:
86258
European-Finnish (FIN)
AF:
0.00938
AC:
501
AN:
53404
Middle Eastern (MID)
AF:
0.00104
AC:
6
AN:
5768
European-Non Finnish (NFE)
AF:
0.00899
AC:
9997
AN:
1112004
Other (OTH)
AF:
0.00679
AC:
410
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.468
Heterozygous variant carriers
0
697
1394
2090
2787
3484
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
350
700
1050
1400
1750
<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:
0.00613
AC:
934
AN:
152336
Hom.:
6
Cov.:
33
AF XY:
0.00584
AC XY:
435
AN XY:
74504
show subpopulations
African (AFR)
AF:
0.00168
AC:
70
AN:
41576
American (AMR)
AF:
0.00196
AC:
30
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.0156
AC:
54
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.000622
AC:
3
AN:
4826
European-Finnish (FIN)
AF:
0.00828
AC:
88
AN:
10626
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.00948
AC:
645
AN:
68034
Other (OTH)
AF:
0.00567
AC:
12
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
55
109
164
218
273
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00789
Hom.:
10
Bravo
AF:
0.00560
Asia WGS
AF:
0.00202
AC:
8
AN:
3478
EpiCase
AF:
0.00791
EpiControl
AF:
0.00759

ClinVar

Significance: Benign
Submissions summary: Uncertain:3Benign:11
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:4
-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Sep 06, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 10, 2015
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:3
Nov 24, 2017
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

DYSF: BS2 -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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. -

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

- -

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

- -

Autosomal recessive limb-girdle muscular dystrophy Benign:1
May 19, 2025
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen
Significance:Benign
Review Status:reviewed by expert panel
Collection Method:curation

The NM_003494.4: c.3534C>T p.(Ile1178=) variant in DYSF, which is also known as NM_001130987.2: c.3588C>T (p.Ile1196=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). The filtering allele frequency for this variant is 0.008874 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 10642/1180038 European (non-Finnish) chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). This variant was detected in a heterozygous state in one individual with suspected LGMD and absent dysferlin expression by blood monocyte assay. No second variant in DYSF was identified, and this individual also had two variants in DNAJB6 (PMID: 25493284, 36983702). The SpliceAI prediction score for this variant is 0.27, which is greater than the VCEP threshold of <0.05 (BP4 not met). However, RNASeq data showed this variant does not affect splicing (PMID: 36983702). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/19/2025): BA1. -

Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
Sep 16, 2020
Natera, Inc.
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Miyoshi muscular dystrophy 1 Benign:1
May 18, 2021
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.27
CADD
Benign
5.3
DANN
Benign
0.70
PhyloP100
-0.62
Mutation Taster
=97/3
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.27
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.27
Position offset: -13

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

Publications

Other links and lift over

dbSNP: rs79899601; hg19: chr2-71825707; API