2-71602794-A-G

Position:

chr2-71602794-A-G

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.3892A>G variant in DYSF, which is also known as NM_001130987.2: c.3946A>G p.(Ile1316Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1298 (p.Ile1298Val). The filtering allele frequency of the variant is 0.006916 for European (non-Finnish) genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 695/152140), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.12 and the computational predictor REVEL gives a score of 0.42. 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/CA179991/MONDO:0015152/180

Frequency

Genomes: 𝑓 0.0046 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0064 ( 46 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:2U:4B:12O:1

Conservation

PhyloP100: 2.67

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:

DYSF (HGNC:):

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.3946A>G	p.Ile1316Val	missense_variant	36/56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 linkuse as main transcript	c.3892A>G	p.Ile1298Val	missense_variant	36/55	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.3946A>G	p.Ile1316Val	missense_variant	36/56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.3892A>G	p.Ile1298Val	missense_variant	36/55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.00457

AC:

695

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00745

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00458

AC:

1141

AN:

248942

Hom.:

AF XY:

0.00471

AC XY:

634

AN XY:

134732

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00141

Gnomad FIN exome

AF:

0.00636

Gnomad NFE exome

AF:

0.00716

Gnomad OTH exome

AF:

0.00430

GnomAD4 exome

AF:

0.00642

AC:

9377

AN:

1461116

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

4619

AN XY:

726746

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00255

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00146

Gnomad4 FIN exome

AF:

0.00600

Gnomad4 NFE exome

AF:

0.00758

Gnomad4 OTH exome

AF:

0.00509

GnomAD4 genome

AF:

0.00456

AC:

695

AN:

152258

Hom.:

Cov.:

AF XY:

0.00450

AC XY:

335

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00650

Gnomad4 NFE

AF:

0.00745

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00558

Hom.:

Bravo

AF:

0.00420

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00451

AC:

547

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00583

EpiControl

AF:

0.00599

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2Uncertain:4Benign:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

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	GeneDx	Apr 10, 2020	This variant is associated with the following publications: (PMID: 24123366, 25898921, 9731526, 25525159, 11468312, 21816046, 22995991, 16934466, 20544924, 30919934, 32528171) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DYSF: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:1Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1998	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: DYSF c.3892A>G (p.Ile1298Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 248942 control chromosomes, predominantly at a frequency of 0.0072 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3892A>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Liu_1998, ten Dam_2019). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: seven classified as likely benign/benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -

Miyoshi muscular dystrophy 1

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1998	- -

Qualitative or quantitative defects of dysferlin

Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Distal myopathy with anterior tibial onset

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

DYSF-related disorder

Uncertain: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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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.3892A>G variant in DYSF, which is also known as NM_001130987.2: c.3946A>G p.(Ile1316Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1298 (p.Ile1298Val). The filtering allele frequency of the variant is 0.006916 for European (non-Finnish) genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 695/152140), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.12 and the computational predictor REVEL gives a score of 0.42. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Benign

0.87

DEOGEN2

Benign

0.17

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

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.017

MetaRNN

Benign

0.013

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

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.46

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

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.25

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

REVEL

Uncertain

0.41

Sift

Benign

0.35

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

Sift4G

Benign

0.57

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

Polyphen

0.0

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

Vest4

0.46

MVP

0.53

MPC

0.12

ClinPred

0.0070

GERP RS

3.2

Varity_R

0.043

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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