rs371227553

Variant names:

• chr2-71658875-C-T
• rs371227553
• NM_001130987.2:c.4756-3C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_001130987.2(DYSF):​c.4756-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,614,178 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: DYSF NM_001130987.2 splice_region, intron
• Scores: Splicing: ADA: 0.004265
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.36
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-71658875-C-T is Benign according to our data. Variant chr2-71658875-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 285982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00138 (210/152296) while in subpopulation AFR AF = 0.00469 (195/41542). AF 95% confidence interval is 0.00416. There are 1 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.4756-3C>T		splice_region intron	N/A	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.4639-3C>T		splice_region intron	N/A	NP_003485.1
	DYSF	NM_001130981.2		c.4753-3C>T		splice_region intron	N/A	NP_001124453.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.4756-3C>T		splice_region intron	N/A	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4639-3C>T		splice_region intron	N/A	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.4753-3C>T		splice_region intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000382 AC: 96 AN: 251318 AF XY: 0.000324

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.000202

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: 0.000163

GnomAD4 exome AF: 0.000151 AC: 221 AN: 1461882 Hom.: 1 Cov.: 31 AF XY: 0.000129 AC XY: 94 AN XY: 727240

African (AFR) AF: 0.00547 AC: 183 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.000430 AC: 26 AN: 60396

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74466

African (AFR) AF: 0.00469 AC: 195 AN: 41542

American (AMR) AF: 0.000719 AC: 11 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00159

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Jul 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DYSF c.4639-3C>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant no significant impact on splicing. One predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00038 in 251318 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYSF causing Autosomal recessive limb-girdle muscular dystrophy type 2B (0.00038 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4639-3C>T in individuals affected with Autosomal recessive limb-girdle muscular dystrophy type 2B and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 285982). Based on the evidence outlined above, the variant was classified as uncertain significance.

Feb 12, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Dec 21, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYSF-related disorder Benign:1

Nov 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Jun 30, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1

Nov 11, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0043
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs371227553; hg19: chr2-71886005;