rs62145939

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_001130987.2(DYSF):c.4848G>A(p.Glu1616Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,614,160 control chromosomes in the GnomAD database, including 487 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 0.016 ( 27 hom., cov: 32)

Exomes 𝑓: 0.023 ( 460 hom. )

Consequence

DYSF
NM_001130987.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 1.68

Publications

5 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 2-71658970-G-A is Benign according to our data. Variant chr2-71658970-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94328.

BP7

Synonymous conserved (PhyloP=1.68 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0162 (2465/152276) while in subpopulation NFE AF = 0.0246 (1673/68008). AF 95% confidence interval is 0.0236. There are 27 homozygotes in GnomAd4. There are 1232 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.4848G>A	p.Glu1616Glu	synonymous_variant	Exon 44 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.4731G>A	p.Glu1577Glu	synonymous_variant	Exon 43 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.4848G>A	p.Glu1616Glu	synonymous_variant	Exon 44 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.4731G>A	p.Glu1577Glu	synonymous_variant	Exon 43 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2467

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00509

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0181

AC:

4548

AN:

251472

AF XY:

0.0188

show subpopulations

Gnomad AFR exome

AF:

0.00406

Gnomad AMR exome

AF:

0.0120

Gnomad ASJ exome

AF:

0.0392

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0159

Gnomad NFE exome

AF:

0.0257

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0234

AC:

34184

AN:

1461884

Hom.:

460

Cov.:

AF XY:

0.0232

AC XY:

16879

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00379

AC:

127

AN:

33480

American (AMR)

AF:

0.0122

AC:

545

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0393

AC:

1028

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0101

AC:

867

AN:

86258

European-Finnish (FIN)

AF:

0.0155

AC:

829

AN:

53420

Middle Eastern (MID)

AF:

0.0251

AC:

145

AN:

5768

European-Non Finnish (NFE)

AF:

0.0263

AC:

29264

AN:

1112006

Other (OTH)

AF:

0.0228

AC:

1377

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2091

4183

6274

8366

10457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1090

2180

3270

4360

5450

<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:

0.0162

AC:

2465

AN:

152276

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1232

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00508

AC:

211

AN:

41556

American (AMR)

AF:

0.0136

AC:

208

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

125

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00706

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0162

AC:

172

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0246

AC:

1673

AN:

68008

Other (OTH)

AF:

0.0166

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

118

236

353

471

589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

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

Alfa

AF:

0.0231

Hom.:

Bravo

AF:

0.0160

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0279

EpiControl

AF:

0.0287

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 29, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 29, 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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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. -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Uncertain:1Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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

- -

not provided

Benign:1

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

5.3

(source)

DANN

Benign

0.53

PhyloP100

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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