rs141867897

Variant names:

• chr2-71553135-T-C
• rs141867897
• NM_001130987.2:c.1931T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1877T>C variant in DYSF, which is also known as NM_001130987.2: c.1931T>C p.(Met644Thr), is a missense variant predicted to cause substitution of methionine by threonine at amino acid 626 (p.Met626Thr). The filtering allele frequency of the variant is 0.002276 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 323/251362), which is higher than the VCEP threshold of 0.001 (BS1). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.12, 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 Likely 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): BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1705983/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (8 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:6
• Conservation: PhyloP100: -0.00800
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BS1: 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.1931T>C	p.Met644Thr	missense	Exon 20 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.1877T>C	p.Met626Thr	missense	Exon 20 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.1928T>C	p.Met643Thr	missense	Exon 20 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.1931T>C	p.Met644Thr	missense	Exon 20 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1877T>C	p.Met626Thr	missense	Exon 20 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.1928T>C	p.Met643Thr	missense	Exon 20 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00128 AC: 323 AN: 251362 AF XY: 0.00130

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00188 AC: 2751 AN: 1461742 Hom.: 8 Cov.: 34 AF XY: 0.00182 AC XY: 1324 AN XY: 727164

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.000582 AC: 31 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00232 AC: 2585 AN: 1111998

Other (OTH) AF: 0.00162 AC: 98 AN: 60396

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000913 AC XY: 68 AN XY: 74488

African (AFR) AF: 0.000168 AC: 7 AN: 41576

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00216 AC: 147 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00179 Hom.: 3

Bravo AF: 0.00110

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00150 AC: 182

EpiCase AF: 0.00174

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.4
DANN	Benign	0.40
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.5	N
PhyloP100		-0.0080
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.054
MVP		0.33
MPC		0.17
ClinPred		0.00096	T
GERP RS		0.97
Varity_R		0.020
gMVP		0.17
Mutation Taster		=100/0	polymorphism

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: rs141867897; hg19: chr2-71780265; COSMIC: COSV106087117;