2-71611333-G-T

Variant names:

• chr2-71611333-G-T
• rs61742872
• NM_001130987.2:c.4046G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP2 BA1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.3992G>T variant in DYSF, which is also known as NM_001130987.2: c.4046G>T p.(Arg1349Leu), is a missense variant predicted to cause substitution of arginine by leucine at amino acid 1331 (p.Arg1331Leu). The filtering allele frequency of the variant is 0.03441 for European (non-Finnish) genome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 943/31374), which is higher than the VCEP threshold of 0.003 (BA1). This variant has also been observed in cis with the variant c.5836_5839del p.(Gln1946TrpfsTer19), which is classified as pathogenic by the ClinGen LGMD VCEP (PMID:19528035) (BP2). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.39, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 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, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147753/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.023 (49 hom., cov: 33)
  • Exomes 𝑓: 0.023 (444 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign reviewed by expert panel B:16
• Conservation: PhyloP100: 3.38
• Publications: 22 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

Specifications for DYSF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.4046G>T	p.Arg1349Leu	missense	Exon 37 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.3992G>T	p.Arg1331Leu	missense	Exon 37 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.4043G>T	p.Arg1348Leu	missense	Exon 37 of 56	NP_001124453.1	O75923-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.4046G>T	p.Arg1349Leu	missense	Exon 37 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.3992G>T	p.Arg1331Leu	missense	Exon 37 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.4043G>T	p.Arg1348Leu	missense	Exon 37 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3567 AN: 152174 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0200 AC: 5004 AN: 250346 AF XY: 0.0196

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0277

Gnomad OTH exome AF: 0.0223

GnomAD4 exome AF: 0.0230 AC: 33595 AN: 1461416 Hom.: 444 Cov.: 33 AF XY: 0.0223 AC XY: 16206 AN XY: 726992

African (AFR) AF: 0.0217 AC: 725 AN: 33470

American (AMR) AF: 0.0108 AC: 485 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 297 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00828 AC: 714 AN: 86238

European-Finnish (FIN) AF: 0.0327 AC: 1748 AN: 53392

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5768

European-Non Finnish (NFE) AF: 0.0255 AC: 28396 AN: 1111646

Other (OTH) AF: 0.0195 AC: 1175 AN: 60364

GnomAD4 genome AF: 0.0234 AC: 3567 AN: 152292 Hom.: 49 Cov.: 33 AF XY: 0.0237 AC XY: 1766 AN XY: 74468

African (AFR) AF: 0.0238 AC: 991 AN: 41562

American (AMR) AF: 0.0161 AC: 247 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4822

European-Finnish (FIN) AF: 0.0334 AC: 355 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0273 AC: 1859 AN: 68026

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.0240 Hom.: 66

Bravo AF: 0.0212

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.0247 AC: 212

ExAC AF: 0.0215 AC: 2613

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.39
Sift	Benign	0.42	T
Sift4G	Benign	0.39	T
Polyphen		0.016	B
Vest4		0.37
MPC		0.24
ClinPred		0.035	T
GERP RS		4.7
Varity_R		0.25
gMVP		0.77
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61742872; hg19: chr2-71838463;