rs17718530

Positions:

Variant summary

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

The NM_001130987.2(DYSF):c.5976A>C(p.Pro1992=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,846 control chromosomes in the GnomAD database, including 46,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1992P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.21 ( 3819 hom., cov: 31)

Exomes 𝑓: 0.24 ( 42899 hom. )

Consequence

DYSF
NM_001130987.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.942

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=-0.82).

BP6

Variant 2-71679148-A-C is Benign according to our data. Variant chr2-71679148-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 94348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71679148-A-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.942 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.254 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.5976A>C	p.Pro1992=	synonymous_variant	53/56	ENST00000410020.8
DYSF	NM_003494.4 linkuse as main transcript	c.5859A>C	p.Pro1953=	synonymous_variant	52/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.5976A>C	p.Pro1992=	synonymous_variant	53/56	1	NM_001130987.2	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.5859A>C	p.Pro1953=	synonymous_variant	52/55	1	NM_003494.4	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.215

AC:

32596

AN:

151952

Hom.:

3815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.351

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.0737

Gnomad SAS

AF:

0.220

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.188

Gnomad NFE

AF:

0.258

Gnomad OTH

AF:

0.198

GnomAD3 exomes

AF:

0.210

AC:

52786

AN:

251424

Hom.:

6281

AF XY:

0.216

AC XY:

29379

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.167

Gnomad AMR exome

AF:

0.0977

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.0726

Gnomad SAS exome

AF:

0.219

Gnomad FIN exome

AF:

0.304

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.237

AC:

345867

AN:

1461774

Hom.:

42899

Cov.:

AF XY:

0.237

AC XY:

172049

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.159

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.147

Gnomad4 EAS exome

AF:

0.0745

Gnomad4 SAS exome

AF:

0.219

Gnomad4 FIN exome

AF:

0.311

Gnomad4 NFE exome

AF:

0.251

Gnomad4 OTH exome

AF:

0.216

GnomAD4 genome

AF:

0.214

AC:

32617

AN:

152072

Hom.:

3819

Cov.:

AF XY:

0.215

AC XY:

15994

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.170

Gnomad4 AMR

AF:

0.142

Gnomad4 ASJ

AF:

0.152

Gnomad4 EAS

AF:

0.0737

Gnomad4 SAS

AF:

0.220

Gnomad4 FIN

AF:

0.297

Gnomad4 NFE

AF:

0.258

Gnomad4 OTH

AF:

0.200

Alfa

AF:

0.237

Hom.:

8713

Bravo

AF:

0.198

Asia WGS

AF:

0.181

AC:

629

AN:

3478

EpiCase

AF:

0.251

EpiControl

AF:

0.243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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.Pro1992Pro in exon 53 of DYSF: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 25.0% (2153/8600) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17718530). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2013	- -
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. -

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 13, 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	- -

Limb-girdle muscular dystrophy, recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 16, 2017

- -

Distal myopathy with anterior tibial onset

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Miyoshi muscular dystrophy 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Miyoshi myopathy

Benign:1

Likely 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

-0.82

CADD

Benign

0.22

DANN

Benign

0.50

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