2-71598577-C-T

Variant names:

• chr2-71598577-C-T
• rs79899601
• NM_001130987.2:c.3588C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.3534C>T p.(Ile1178=) variant in DYSF, which is also known as NM_001130987.2: c.3588C>T (p.Ile1196=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). The filtering allele frequency for this variant is 0.008874 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 10642/1180038 European (non-Finnish) chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). This variant was detected in a heterozygous state in one individual with suspected LGMD and absent dysferlin expression by blood monocyte assay. No second variant in DYSF was identified, and this individual also had two variants in DNAJB6 (PMID:25493284, 36983702). The SpliceAI prediction score for this variant is 0.27, which is greater than the VCEP threshold of <0.05 (BP4 not met). However, RNASeq data showed this variant does not affect splicing (PMID:36983702). In summary, this variant meets the criteria to be classified as 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; 05/19/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA152665/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (53 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign reviewed by expert panel U:3 B:11
• Conservation: PhyloP100: -0.617
• 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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: Benign. The variant received -8 ACMG points.

• BA1: 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.3588C>T	p.Ile1196Ile	synonymous	Exon 33 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.3534C>T	p.Ile1178Ile	synonymous	Exon 33 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.3585C>T	p.Ile1195Ile	synonymous	Exon 33 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.3588C>T	p.Ile1196Ile	synonymous	Exon 33 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.3534C>T	p.Ile1178Ile	synonymous	Exon 33 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.3585C>T	p.Ile1195Ile	synonymous	Exon 33 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 934 AN: 152218 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00948

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00666 AC: 1673 AN: 251142 AF XY: 0.00678

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00827

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00787 AC: 11498 AN: 1461862 Hom.: 53 Cov.: 32 AF XY: 0.00790 AC XY: 5747 AN XY: 727226

African (AFR) AF: 0.00128 AC: 43 AN: 33480

American (AMR) AF: 0.00186 AC: 83 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 300 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00179 AC: 154 AN: 86258

European-Finnish (FIN) AF: 0.00938 AC: 501 AN: 53404

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00899 AC: 9997 AN: 1112004

Other (OTH) AF: 0.00679 AC: 410 AN: 60394

GnomAD4 genome AF: 0.00613 AC: 934 AN: 152336 Hom.: 6 Cov.: 33 AF XY: 0.00584 AC XY: 435 AN XY: 74504

African (AFR) AF: 0.00168 AC: 70 AN: 41576

American (AMR) AF: 0.00196 AC: 30 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00828 AC: 88 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00948 AC: 645 AN: 68034

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00789 Hom.: 10

Bravo AF: 0.00560

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.00791

EpiControl AF: 0.00759

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	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	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Miyoshi muscular dystrophy 1 (1)
-	1	-	Miyoshi myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	5.3
DANN	Benign	0.70
PhyloP100		-0.62
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -13

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

Other links and lift over

dbSNP: rs79899601; hg19: chr2-71825707;