chr2-71535283-G-A

Position:

chr2-71535283-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1369G>A variant in DYSF, which is also known as NM_001130987.2: c.1465G>A (p.Glu489Lys), is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 457 (p.Glu457Lys). The filtering allele frequency of the variant is 0.02368 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 4291/251472), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.28 and the computational predictor REVEL gives a score of 0.41. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147721/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.017 ( 30 hom., cov: 31)

Exomes 𝑓: 0.020 ( 372 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:13

Conservation

PhyloP100: 8.91

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 -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.1465G>A	p.Glu489Lys	missense_variant	16/56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 linkuse as main transcript	c.1369G>A	p.Glu457Lys	missense_variant	15/55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.1465G>A	p.Glu489Lys	missense_variant	16/56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.1369G>A	p.Glu457Lys	missense_variant	15/55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2611

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.0314

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0171

AC:

4291

AN:

251472

Hom.:

AF XY:

0.0174

AC XY:

2362

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00431

Gnomad AMR exome

AF:

0.00847

Gnomad ASJ exome

AF:

0.0274

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00728

Gnomad FIN exome

AF:

0.0255

Gnomad NFE exome

AF:

0.0244

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0202

AC:

29528

AN:

1461776

Hom.:

372

Cov.:

AF XY:

0.0200

AC XY:

14532

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00323

Gnomad4 AMR exome

AF:

0.00988

Gnomad4 ASJ exome

AF:

0.0294

Gnomad4 EAS exome

AF:

0.000554

Gnomad4 SAS exome

AF:

0.00751

Gnomad4 FIN exome

AF:

0.0237

Gnomad4 NFE exome

AF:

0.0225

Gnomad4 OTH exome

AF:

0.0189

GnomAD4 genome

AF:

0.0171

AC:

2608

AN:

152134

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1261

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00448

Gnomad4 AMR

AF:

0.0146

Gnomad4 ASJ

AF:

0.0337

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.0314

Gnomad4 NFE

AF:

0.0244

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.0233

Hom.:

Bravo

AF:

0.0158

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0245

AC:

211

ExAC

AF:

0.0170

AC:

2065

EpiCase

AF:

0.0267

EpiControl

AF:

0.0273

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2012	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DYSF: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 25312915, 22995991, 31862442, 20981092, 17698709, 27884173, 21522182, 25214167) -

Qualitative or quantitative defects of dysferlin

Uncertain:1Benign:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 08, 2025

The NM_003494.4: c.1369G>A variant in DYSF, which is also known as NM_001130987.2: c.1465G>A (p.Glu489Lys), is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 457 (p.Glu457Lys). The filtering allele frequency of the variant is 0.02368 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 4291/251472), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.28 and the computational predictor REVEL gives a score of 0.41. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

.;.;.;.;D;.;.;.;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0098

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.4

.;.;L;.;L;.;.;.;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.1

D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.030

D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.99

D;D;D;D;D;D;D;D;D;D;D

Vest4

0.43

MPC

0.58

ClinPred

0.030

GERP RS

4.8

Varity_R

0.74

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: -15

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