rs2303596

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.1881T>C(p.Asp627=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,613,950 control chromosomes in the GnomAD database, including 395,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 38068 hom., cov: 32)

Exomes 𝑓: 0.69 ( 357627 hom. )

Consequence

DYSF
NM_001130987.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -2.58

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=-0.59).

BP6

Variant 2-71553085-T-C is Benign according to our data. Variant chr2-71553085-T-C is described in ClinVar as [Benign]. Clinvar id is 94281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71553085-T-C is described in Lovd as [Benign]. Variant chr2-71553085-T-C is described in Lovd as [Pathogenic].

BP7

Synonymous conserved (PhyloP=-2.58 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.1881T>C	p.Asp627=	synonymous_variant	20/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.1827T>C	p.Asp609=	synonymous_variant	20/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.1881T>C	p.Asp627=	synonymous_variant	20/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.1827T>C	p.Asp609=	synonymous_variant	20/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

106068

AN:

151996

Hom.:

38021

Cov.:

show subpopulations

Gnomad AFR

AF:

0.779

Gnomad AMI

AF:

0.776

Gnomad AMR

AF:

0.635

Gnomad ASJ

AF:

0.754

Gnomad EAS

AF:

0.198

Gnomad SAS

AF:

0.502

Gnomad FIN

AF:

0.687

Gnomad MID

AF:

0.704

Gnomad NFE

AF:

0.712

Gnomad OTH

AF:

0.695

GnomAD3 exomes

AF:

0.641

AC:

161254

AN:

251388

Hom.:

54563

AF XY:

0.640

AC XY:

86955

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.784

Gnomad AMR exome

AF:

0.617

Gnomad ASJ exome

AF:

0.743

Gnomad EAS exome

AF:

0.173

Gnomad SAS exome

AF:

0.539

Gnomad FIN exome

AF:

0.689

Gnomad NFE exome

AF:

0.712

Gnomad OTH exome

AF:

0.666

GnomAD4 exome

AF:

0.692

AC:

1012266

AN:

1461834

Hom.:

357627

Cov.:

AF XY:

0.689

AC XY:

500766

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.784

Gnomad4 AMR exome

AF:

0.624

Gnomad4 ASJ exome

AF:

0.743

Gnomad4 EAS exome

AF:

0.214

Gnomad4 SAS exome

AF:

0.542

Gnomad4 FIN exome

AF:

0.695

Gnomad4 NFE exome

AF:

0.721

Gnomad4 OTH exome

AF:

0.678

GnomAD4 genome

AF:

0.698

AC:

106173

AN:

152116

Hom.:

38068

Cov.:

AF XY:

0.688

AC XY:

51139

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.779

Gnomad4 AMR

AF:

0.635

Gnomad4 ASJ

AF:

0.754

Gnomad4 EAS

AF:

0.198

Gnomad4 SAS

AF:

0.503

Gnomad4 FIN

AF:

0.687

Gnomad4 NFE

AF:

0.712

Gnomad4 OTH

AF:

0.691

Alfa

AF:

0.710

Hom.:

63844

Bravo

AF:

0.699

Asia WGS

AF:

0.389

AC:

1357

AN:

3478

EpiCase

AF:

0.715

EpiControl

AF:

0.716

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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+	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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.Asp627Asp in exon 20 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 29.0% (2493/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2303596). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 17, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:2

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

Qualitative or quantitative defects of dysferlin

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Limb-girdle muscular dystrophy, recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

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

-0.59

CADD

Benign

0.79

DANN

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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