rs398123763

Variant names:

• chr2-71520905-G-A
• rs398123763
• NM_001130987.2:c.1149+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-71520905-G-A
• chr2-71520905-G-C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PVS1_Strong PM3_Supporting PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1053+1G>A variant in DYSF, which is also known as NM_001130987.2: c.1149+1G>A, occurs within the canonical splice donor site of intron 11. RNAseq analysis has shown that this variant disrupts splicing, resulting in two different frameshifts and premature truncations, p.Arg313ProfsTer8 and p.His314GlufsTer9, as well as an inframe deletion of 66 amino acids, p.Val286_Pro351del (PMID:36983702; PVS1_Strong_RNA). This variant has been identified in at least four individuals with LGMD (PMID:27602406; 24488599; 36983702), including in unknown phase with a pathogenic variant (NM_003494.4: c.610C>T p.(Arg204Ter), 0.5 pts, PMID:27602406; PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID:36983702; PP4_Strong). Another nucleotide change affecting the same splice motif, NM_003494.4: c.1053+5G>A, has also been shown to result in skipping of exon 11 and is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. The filtering allele frequency of this variant is 0.000006973 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/1111878 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (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; 04/17/2025): PVS1_Strong_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA222120/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DYSF NM_001130987.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 9.88
• Publications: 2 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 10 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.
• 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.1149+1G>A		splice_donor intron	N/A	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.1053+1G>A		splice_donor intron	N/A	NP_003485.1
	DYSF	NM_001130981.2		c.1146+1G>A		splice_donor intron	N/A	NP_001124453.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.1149+1G>A		splice_donor intron	N/A	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1053+1G>A		splice_donor intron	N/A	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.1146+1G>A		splice_donor intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152192 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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461702 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000315 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.9
GERP RS		5.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: -1

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

Other links and lift over

dbSNP: rs398123763; hg19: chr2-71748035;