rs398123779

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_001130987.2(DYSF):c.3245_3250dupCGGAGG(p.Ala1082_Glu1083dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.05 in 1,613,284 control chromosomes in the GnomAD database, including 2,265 homozygotes. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. G1084G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.040 ( 157 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2108 hom. )

Consequence

DYSF
NM_001130987.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:15

Conservation

PhyloP100: 4.19

Publications

7 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

DYSF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001130987.2.

BP6

Variant 2-71574204-C-CAGGCGG is Benign according to our data. Variant chr2-71574204-C-CAGGCGG is described in ClinVar as Benign. ClinVar VariationId is 94301.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.3245_3250dupCGGAGG	p.Ala1082_Glu1083dup	disruptive_inframe_insertion	Exon 30 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.3191_3196dupCGGAGG	p.Ala1064_Glu1065dup	disruptive_inframe_insertion	Exon 30 of 55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.3245_3250dupCGGAGG	p.Ala1082_Glu1083dup	disruptive_inframe_insertion	Exon 30 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.3191_3196dupCGGAGG	p.Ala1064_Glu1065dup	disruptive_inframe_insertion	Exon 30 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0405

AC:

6164

AN:

152198

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0113

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.0561

Gnomad ASJ

AF:

0.0449

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0225

Gnomad FIN

AF:

0.0337

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0587

Gnomad OTH

AF:

0.0532

GnomAD2 exomes

AF:

0.0395

AC:

9796

AN:

248130

AF XY:

0.0412

show subpopulations

Gnomad AFR exome

AF:

0.00835

Gnomad AMR exome

AF:

0.0359

Gnomad ASJ exome

AF:

0.0488

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0299

Gnomad NFE exome

AF:

0.0560

Gnomad OTH exome

AF:

0.0490

GnomAD4 exome

AF:

0.0510

AC:

74557

AN:

1460968

Hom.:

2108

Cov.:

AF XY:

0.0505

AC XY:

36713

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.00875

AC:

293

AN:

33480

American (AMR)

AF:

0.0379

AC:

1695

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0462

AC:

1208

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0240

AC:

2070

AN:

86256

European-Finnish (FIN)

AF:

0.0299

AC:

1573

AN:

52622

Middle Eastern (MID)

AF:

0.0718

AC:

414

AN:

5764

European-Non Finnish (NFE)

AF:

0.0577

AC:

64199

AN:

1111908

Other (OTH)

AF:

0.0514

AC:

3101

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

3722

7444

11167

14889

18611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2304

4608

6912

9216

11520

<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:

0.0405

AC:

6163

AN:

152316

Hom.:

157

Cov.:

AF XY:

0.0399

AC XY:

2971

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0113

AC:

470

AN:

41592

American (AMR)

AF:

0.0561

AC:

858

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0449

AC:

156

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0226

AC:

109

AN:

4832

European-Finnish (FIN)

AF:

0.0337

AC:

358

AN:

10618

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0587

AC:

3989

AN:

68004

Other (OTH)

AF:

0.0527

AC:

111

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

307

614

920

1227

1534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0486

Hom.:

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0632

EpiControl

AF:

0.0611

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 19, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala1082_Glu1083dup in exon 30 of DYSF: This variant is a duplication of 2 amin o acids at position 1082 and is not predicted to alter the protein reading-frame . This variant is not expected to have clinical significance because it has been identified in 5.6% (453/8150) of European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/). -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19528035, 15469449, 14678801, 31862442) -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Mar 14, 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.3191_3196dup p.(Glu1065_Gly1066insAlaGlu) variant in DYSF, which is also known as NM_001130987.2: c.3245_3250dup p.(Glu1083_Gly1084insAlaGlu), is predicted to cause a change in the length of the protein due to an in-frame insertion of two amino acids in a non-repeat region (PM4). The filtering allele frequency for this variant is 0.05714 in the European (non-Finnish) population of gnomAD v4.1.0 (the lower threshold of the 95% CI of 3989/68004 genome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of ≥0.003 for BA1 (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/14/2025): BA1, PM4. -

Limb-girdle muscular dystrophy, recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Distal myopathy with anterior tibial onset

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Miyoshi muscular dystrophy 1

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Miyoshi myopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.2

Mutation Taster

=63/37

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over