rs745891180

Variant names:

• chr2-71664443-G-A
• rs745891180
• NM_001130987.2:c.5174+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-71664443-G-A
• chr2-71664443-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2_Supporting PM3_Supporting PP1_Moderate PP4_Moderate PVS1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.5057+5G>A variant in DYSF, which is also known as NM_001130987.2: c.5174+5G>A, occurs within the splice donor motif of intron 45. RNAseq and cDNA analysis has demonstrated that this variant disrupts splicing, resulting in a frameshift and premature truncation, with no detectable normally spliced transcript (PMID:36983702, 10766988; PVS1_RNA). This variant has been identified in at least two patients with LGMD, including in a homozygous state (0.25 pts, PMID:10766988) and in unknown phase with a pathogenic variant (c.5979dup p.(Glu1994ArgfsTer3), 0.5 pts, PMID:36983702) (PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Moderate, PMID:36983702, 10766988). The variant was shown to co-segregate with the LGMD phenotype in five affected members of a consanguineous family of Yemenite Jewish descent (PP1_Moderate; PMID:10766988). The highest population minor allele frequency is 0.00002196 (2/91068 exome alleles) in the South Asian population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (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; 03/18/2025): PVS1_RNA, PM3_Supporting, PP4_Moderate, PP1_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA253906/MONDO:0015152/180

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DYSF NM_001130987.2 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 5.77
• 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 14 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.5174+5G>A		splice_region intron	N/A	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.5057+5G>A		splice_region intron	N/A	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.5171+5G>A		splice_region 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.5174+5G>A		splice_region intron	N/A	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.5057+5G>A		splice_region intron	N/A	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.5171+5G>A		splice_region intron	N/A	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251286 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461662 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33466

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: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive limb-girdle muscular dystrophy (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2B (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	-0.17
CADD	Uncertain	24
DANN	Benign	0.97
PhyloP100		5.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -9
DS_DL_spliceai		0.71		Position offset: -5

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

Other links and lift over

dbSNP: rs745891180; hg19: chr2-71891573; COSMIC: COSV50293567;