2-71661900-G-T

Variant names:

• chr2-71661900-G-T
• rs886042110
• NM_001130987.2:c.5003+1249G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP1 PM2_Supporting PM3_Strong PVS1_Moderate PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.4886+1249G>T variant in DYSF, which is also known as NM_001130987.2: c.5003+1249G>T, is a deep intronic variant. SpliceAI gives a score of 0.26 for donor gain and 0.12 for acceptor gain. RNAseq analysis has demonstrated two splice effects of this variant: activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 177 bp intronic sequence and a non-frameshifting insertion of 59 amino acids, p.Lys1646_Met1647ins59; and activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 88 bp of intronic sequence and a frameshift with nonsense mediated decay expected, p.Lys1646AsnfsTer13 (PMID:36983702; PVS1_Moderate_RNA). This variant has been reported in at least four individuals with features consistent with LGMD (PMID:26273692, 36983702, 30564623, 25493284), including confirmed in trans with a likely pathogenic or pathogenic variant in one patient (NM_003494.4: c.1168G>A p.(Asp390Asn), 1.0 pt, PMID:26273692) and in unknown phase with a pathogenic variant in two patients (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID:36983702, 30564623, 25493284; NM_003494.4: c.1834C>T p.(Gln612Ter), 0.5 pts, PMID:25493284) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF showed progressive muscle weakness and absent dysferlin protein expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PMID:36983702, 25493284; PP4_Strong). In addition, this variant has been shown to co-segregate with the LGMD phenotype in one affected family member (PMID:30564623, 30564623) (PP1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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; 04/23/2025): PVS1_Moderate_RNA, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603819/MONDO:0015152/180

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 0.168
• Publications: 8 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.5003+1249G>T		intron	N/A	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.4886+1249G>T		intron	N/A	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.5000+1249G>T		intron	N/A	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.5003+1249G>T		intron	N/A	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4886+1249G>T		intron	N/A	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.5000+1249G>T		intron	N/A	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		0.17
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: -2

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

Other links and lift over

dbSNP: rs886042110; hg19: chr2-71889030;