rs2288355

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001130987.2(DYSF):c.2637A>T(p.Ser879=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,613,856 control chromosomes in the GnomAD database, including 355,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S879S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.68 ( 36031 hom., cov: 31)

Exomes 𝑓: 0.65 ( 318992 hom. )

Consequence

DYSF
NM_001130987.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.563

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 made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 2-71568022-A-T is Benign according to our data. Variant chr2-71568022-A-T is described in ClinVar as [Benign]. Clinvar id is 94290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71568022-A-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.563 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.2637A>T	p.Ser879=	synonymous_variant	25/56	ENST00000410020.8
DYSF	NM_003494.4 linkuse as main transcript	c.2583A>T	p.Ser861=	synonymous_variant	25/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.2637A>T	p.Ser879=	synonymous_variant	25/56	1	NM_001130987.2	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.2583A>T	p.Ser861=	synonymous_variant	25/55	1	NM_003494.4	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.677

AC:

102788

AN:

151858

Hom.:

35982

Cov.:

show subpopulations

Gnomad AFR

AF:

0.810

Gnomad AMI

AF:

0.624

Gnomad AMR

AF:

0.595

Gnomad ASJ

AF:

0.653

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.633

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.677

Gnomad OTH

AF:

0.642

GnomAD3 exomes

AF:

0.597

AC:

150047

AN:

251476

Hom.:

47978

AF XY:

0.594

AC XY:

80700

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.809

Gnomad AMR exome

AF:

0.524

Gnomad ASJ exome

AF:

0.627

Gnomad EAS exome

AF:

0.155

Gnomad SAS exome

AF:

0.482

Gnomad FIN exome

AF:

0.643

Gnomad NFE exome

AF:

0.678

Gnomad OTH exome

AF:

0.621

GnomAD4 exome

AF:

0.652

AC:

953457

AN:

1461882

Hom.:

318992

Cov.:

AF XY:

0.648

AC XY:

471009

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.822

Gnomad4 AMR exome

AF:

0.539

Gnomad4 ASJ exome

AF:

0.642

Gnomad4 EAS exome

AF:

0.179

Gnomad4 SAS exome

AF:

0.488

Gnomad4 FIN exome

AF:

0.655

Gnomad4 NFE exome

AF:

0.683

Gnomad4 OTH exome

AF:

0.630

GnomAD4 genome

AF:

0.677

AC:

102891

AN:

151974

Hom.:

36031

Cov.:

AF XY:

0.667

AC XY:

49524

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.811

Gnomad4 AMR

AF:

0.595

Gnomad4 ASJ

AF:

0.653

Gnomad4 EAS

AF:

0.175

Gnomad4 SAS

AF:

0.462

Gnomad4 FIN

AF:

0.633

Gnomad4 NFE

AF:

0.677

Gnomad4 OTH

AF:

0.639

Alfa

AF:

0.677

Hom.:

11363

Bravo

AF:

0.678

Asia WGS

AF:

0.386

AC:

1344

AN:

3478

EpiCase

AF:

0.673

EpiControl

AF:

0.672

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ser879Ser in exon 25 of DYSF: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 33.1% (2848/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2288355). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Qualitative or quantitative defects of dysferlin

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Distal myopathy with anterior tibial onset

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Limb-Girdle Muscular Dystrophy, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 16, 2019

- -

Miyoshi muscular dystrophy 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Miyoshi myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

Cadd

Benign

6.5

Dann

Benign

0.66

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