2-71659033-G-T

Variant names:

• chr2-71659033-G-T
• rs141704244
• NM_001130987.2:c.4911G>T

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PM3 PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.4794G>T variant in DYSF, which is also known as NM_001130987.2: c.4911G>T (p.Lys1637Asn), is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 1598, p.(Lys1598Asn). This variant affects the last residue in exon 45 and is predicted to disrupt the consensus splice donor site (SpliceAI delta score 0.33) and strengthen an alternative splice site in the intron (SpliceAI delta score 0.63) (PP3). RNAseq analysis has demonstrated that this variant has a leaky splice effect, resulting in skipping of exon 43 and an inframe deletion, p.Gly1547_Lys1598del, in a subset of transcripts (PMID:36983702). This variant has been detected in nine individuals with features consistent with LGMD (PMID:33144682; 33610434; 30564623; 36983702; 27195159; ClinVar SCV005360734.1 internal data communication; LOVD DYSF_000170), including confirmed in trans with a likely pathogenic or pathogenic variant in two patients (NM_003494.4: c.4756C>T, p.(Arg1586Ter), 1.0 pt, LOVD Individual #00215321; NM_003494.4: c.6124C>T p.(Arg2042Cys), 1.0 pt, ClinVar SCV005360734.1 internal data communication). In at least four patients, it was reported in unknown phase with a pathogenic variant (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID:36983702); (NM_003494.4: c.6124C>T p.(Arg2042Cys), 0.5 pts x2, PMID:36983702; PMID:30564623; LOVD Individual #00220316); (NM_003494.4: c.755C>T p.(Thr252Met), 0.5 pts, PMID:30564623; LOVD Individual #00219977) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF displayed a progressive limb girdle pattern of weakness and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong, PMID:27195159). The filtering allele frequency of this variant is 0.0002 for gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 201/1112000 European (non-Finnish) chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (criterion not met). The Lys1598Asn protein was classified as functional in both 2A and ICC assays of dysferlin membrane localization (PMID:35028538), and the REVEL score is 0.387. In summary, this variant meets the criteria to be classified as Pathogenic 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; 06/24/2025): PP3, PM3_Very Strong, PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA222176/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:2 O:1
• Conservation: PhyloP100: 8.09
• Publications: 6 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: Pathogenic. The variant received 7 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.4911G>T	p.Lys1637Asn	missense splice_region	Exon 44 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.4794G>T	p.Lys1598Asn	missense splice_region	Exon 43 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.4908G>T	p.Lys1636Asn	missense splice_region	Exon 44 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.4911G>T	p.Lys1637Asn	missense splice_region	Exon 44 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4794G>T	p.Lys1598Asn	missense splice_region	Exon 43 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.4908G>T	p.Lys1636Asn	missense splice_region	Exon 44 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251434 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000144 AC: 211 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.000131 AC XY: 95 AN XY: 727234

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53402

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

European-Non Finnish (NFE) AF: 0.000181 AC: 201 AN: 1112000

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy (2)
2	-	-	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
1	-	-	Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 (1)
1	-	-	DYSF-related disorder (2)
1	-	-	Miyoshi muscular dystrophy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.0029	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.39
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.76	P
Vest4		0.70
MutPred		0.50		Loss of methylation at K1598 (P = 0.0011)
MVP		0.82
MPC		0.52
ClinPred		0.46	T
GERP RS		4.8
Varity_R		0.38
gMVP		0.63
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.63		Position offset: 45
DS_DL_spliceai		0.33		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141704244; hg19: chr2-71886163; COSMIC: COSV99247648;