rs34671418

Positions:

chr2-71564202-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.2500A>G variant in DYSF, which is also known as NM_001130987.2: c.2554A>G p.(Ile852Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 834 (p.Ile834Val). The filtering allele frequency of the variant is 0.08367 for African/African American genome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 1541/31380), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0, which suggests it does not impact splicing and is below the LGMD VCEP threshold of ≤0.05. The computational predictor REVEL gives a score of 0.08, which is below the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1) (BP4). 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, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147734/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.041 ( 191 hom., cov: 33)

Exomes 𝑓: 0.024 ( 575 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: 2.92

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 -9 ACMG points.

BP4

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

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.2554A>G	p.Ile852Val	missense_variant	24/56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 linkuse as main transcript	c.2500A>G	p.Ile834Val	missense_variant	24/55	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.2554A>G	p.Ile852Val	missense_variant	24/56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.2500A>G	p.Ile834Val	missense_variant	24/55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0406

AC:

6172

AN:

152184

Hom.:

190

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0852

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0184

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0272

Gnomad OTH

AF:

0.0253

GnomAD3 exomes

AF:

0.0232

AC:

5833

AN:

251470

Hom.:

131

AF XY:

0.0216

AC XY:

2936

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0855

Gnomad AMR exome

AF:

0.00948

Gnomad ASJ exome

AF:

0.0271

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0268

Gnomad OTH exome

AF:

0.0204

GnomAD4 exome

AF:

0.0241

AC:

35283

AN:

1461878

Hom.:

575

Cov.:

AF XY:

0.0232

AC XY:

16867

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0882

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.0263

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.0325

Gnomad4 NFE exome

AF:

0.0251

Gnomad4 OTH exome

AF:

0.0235

GnomAD4 genome

AF:

0.0407

AC:

6198

AN:

152302

Hom.:

191

Cov.:

AF XY:

0.0401

AC XY:

2985

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0856

Gnomad4 AMR

AF:

0.0184

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0364

Gnomad4 NFE

AF:

0.0272

Gnomad4 OTH

AF:

0.0251

Alfa

AF:

0.0276

Hom.:

170

Bravo

AF:

0.0400

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.0819

AC:

361

ESP6500EA

AF:

0.0230

AC:

198

ExAC

AF:

0.0258

AC:

3132

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0242

EpiControl

AF:

0.0216

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 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	PreventionGenetics, part of Exact Sciences	-	- -
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	Eurofins Ntd Llc (ga)	Jul 12, 2012	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Qualitative or quantitative defects of dysferlin

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Limb-girdle muscular dystrophy, recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.21

.;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.93

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

MetaRNN

Benign

0.0033

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

.;.;N;.;N;.;.;.;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.34

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.077

Sift

Benign

0.26

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

Sift4G

Benign

0.35

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

Polyphen

0.050

B;B;B;B;B;B;B;B;B;B;B

Vest4

0.21

MPC

0.13

ClinPred

0.0065

GERP RS

2.4

Varity_R

0.033

gMVP

0.28

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