chr2-71602794-A-G

Variant names:

• chr2-71602794-A-G
• rs121908954
• NM_001130987.2:c.3946A>G

Variant summary

Our verdict is Benign. The variant received -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
• Clinical Significance: Benign reviewed by expert panel P:2 U:4 B:12 O:1
• Conservation: PhyloP100: 2.67
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuromuscular disease caused by qualitative or quantitative defects of dysferlin

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• autosomal recessive limb-girdle muscular dystrophy type 2B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• distal myopathy with anterior tibial onset

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy, Paradas type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Miyoshi myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.3946A>G	p.Ile1316Val	missense_variant	Exon 36 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.3892A>G	p.Ile1298Val	missense_variant	Exon 36 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.3946A>G	p.Ile1316Val	missense_variant	Exon 36 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.3892A>G	p.Ile1298Val	missense_variant	Exon 36 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 695 AN: 152140 Hom.: 3 Cov.: 32

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

GnomAD2 exomes AF: 0.00458 AC: 1141 AN: 248942 AF XY: 0.00471

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 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.: 46 Cov.: 31 AF XY: 0.00636 AC XY: 4619 AN XY: 726746

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00255 AC: 114 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00146 AC: 126 AN: 86084

European-Finnish (FIN) AF: 0.00600 AC: 318 AN: 53036

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.00758 AC: 8429 AN: 1111890

Other (OTH) AF: 0.00509 AC: 307 AN: 60362

GnomAD4 genome AF: 0.00456 AC: 695 AN: 152258 Hom.: 3 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74474

African (AFR) AF: 0.00130 AC: 54 AN: 41546

American (AMR) AF: 0.00294 AC: 45 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00745 AC: 507 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00565 Hom.: 6

Bravo AF: 0.00420

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00451 AC: 547

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00599

ClinVar

Significance: Benign

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

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:5

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 10, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24123366, 25898921, 9731526, 25525159, 11468312, 21816046, 22995991, 16934466, 20544924, 30919934, 32528171) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYSF: BP4, BS2 -

Sep 28, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:1 Uncertain:1 Benign:2

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 1 Pathogenic:1 Uncertain:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Benign:1 Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Distal myopathy with anterior tibial onset Uncertain:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DYSF-related disorder Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 08, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Benign	0.87
DEOGEN2	Benign	0.17	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.46	.;.;N;.;N;.;.;.;.;.;.
PhyloP100		2.7
PrimateAI	Uncertain	0.50	T
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	T
GERP RS		3.2
Varity_R		0.043
gMVP		0.23
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121908954; hg19: chr2-71829924; COSMIC: COSV105093727; COSMIC: COSV105093727;