rs34603128

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001130987.2(DYSF):c.396C>T(p.Pro132Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,551,400 control chromosomes in the GnomAD database, including 12,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1677 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10355 hom. )

Consequence

DYSF
NM_001130987.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.263

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 2-71511857-C-T is Benign according to our data. Variant chr2-71511857-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71511857-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.263 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.396C>T	p.Pro132Pro	synonymous_variant	Exon 5 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.393C>T	p.Pro131Pro	synonymous_variant	Exon 5 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.396C>T	p.Pro132Pro	synonymous_variant	Exon 5 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.393C>T	p.Pro131Pro	synonymous_variant	Exon 5 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21070

AN:

152118

Hom.:

1675

Cov.:

show subpopulations

Gnomad AFR

AF:

0.200

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.0602

Gnomad EAS

AF:

0.0123

Gnomad SAS

AF:

0.0513

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.126

Gnomad OTH

AF:

0.143

GnomAD2 exomes

AF:

0.104

AC:

16380

AN:

156760

AF XY:

0.102

show subpopulations

Gnomad AFR exome

AF:

0.202

Gnomad AMR exome

AF:

0.0899

Gnomad ASJ exome

AF:

0.0664

Gnomad EAS exome

AF:

0.0106

Gnomad FIN exome

AF:

0.137

Gnomad NFE exome

AF:

0.128

Gnomad OTH exome

AF:

0.110

GnomAD4 exome

AF:

0.117

AC:

164029

AN:

1399164

Hom.:

10355

Cov.:

AF XY:

0.115

AC XY:

79441

AN XY:

690112

show subpopulations

Gnomad4 AFR exome

AF:

0.205

AC:

6464

AN:

31592

Gnomad4 AMR exome

AF:

0.0932

AC:

3327

AN:

35706

Gnomad4 ASJ exome

AF:

0.0674

AC:

1697

AN:

25182

Gnomad4 EAS exome

AF:

0.00646

AC:

231

AN:

35738

Gnomad4 SAS exome

AF:

0.0589

AC:

4664

AN:

79232

Gnomad4 FIN exome

AF:

0.133

AC:

6564

AN:

49216

Gnomad4 NFE exome

AF:

0.124

AC:

133934

AN:

1078800

Gnomad4 Remaining exome

AF:

0.113

AC:

6551

AN:

58008

Heterozygous variant carriers

7648

15296

22945

30593

38241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

4858

9716

14574

19432

24290

<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:

0.139

AC:

21090

AN:

152236

Hom.:

1677

Cov.:

AF XY:

0.137

AC XY:

10181

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.200

AC:

0.199928

AN:

0.199928

Gnomad4 AMR

AF:

0.121

AC:

0.120751

AN:

0.120751

Gnomad4 ASJ

AF:

0.0602

AC:

0.0601959

AN:

0.0601959

Gnomad4 EAS

AF:

0.0125

AC:

0.0125434

AN:

0.0125434

Gnomad4 SAS

AF:

0.0505

AC:

0.0505385

AN:

0.0505385

Gnomad4 FIN

AF:

0.136

AC:

0.135644

AN:

0.135644

Gnomad4 NFE

AF:

0.126

AC:

0.125614

AN:

0.125614

Gnomad4 OTH

AF:

0.141

AC:

0.141098

AN:

0.141098

Heterozygous variant carriers

917

1833

2750

3666

4583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

226

452

678

904

1130

<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:

0.130

Hom.:

878

Bravo

AF:

0.142

Asia WGS

AF:

0.0420

AC:

148

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jan 30, 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. -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro132Pro in exon 5 of DYSF: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 16.8% (663/3952) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34603128). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 24, 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:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Qualitative or quantitative defects of dysferlin

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Miyoshi muscular dystrophy 1

Benign:1

Jun 10, 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

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.0

DANN

Benign

0.84

Mutation Taster

=100/0

polymorphism (auto)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over