2-71553118-C-T

Variant names:

• chr2-71553118-C-T
• rs35721373
• NM_001130987.2:c.1914C>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.1860C>T (p.Tyr620=) variant in DYSF, which is also known as NM_001130987.2: c.1914C>T (p.Tyr638=), 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 is 0.05612 for South Asian exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 1787/30616), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI prediction score for this variant is 0.08, which is greater than the VCEP threshold of <0.05 (BP4 and BP7 not applied). 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; 01/08/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147728/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.033 (95 hom., cov: 33)
  • Exomes 𝑓: 0.030 (818 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:17
• Conservation: PhyloP100: -3.52
• Publications: 6 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.1914C>T	p.Tyr638Tyr	synonymous	Exon 20 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.1860C>T	p.Tyr620Tyr	synonymous	Exon 20 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.1911C>T	p.Tyr637Tyr	synonymous	Exon 20 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.1914C>T	p.Tyr638Tyr	synonymous	Exon 20 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1860C>T	p.Tyr620Tyr	synonymous	Exon 20 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.1911C>T	p.Tyr637Tyr	synonymous	Exon 20 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 5030 AN: 152192 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.0585

Gnomad FIN AF: 0.00913

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0302

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0286 AC: 7180 AN: 251438 AF XY: 0.0300

Gnomad AFR exome AF: 0.0528

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.00837

Gnomad FIN exome AF: 0.00711

Gnomad NFE exome AF: 0.0298

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0300 AC: 43914 AN: 1461820 Hom.: 818 Cov.: 34 AF XY: 0.0310 AC XY: 22569 AN XY: 727210

African (AFR) AF: 0.0550 AC: 1841 AN: 33480

American (AMR) AF: 0.0148 AC: 660 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 567 AN: 26136

East Asian (EAS) AF: 0.00844 AC: 335 AN: 39700

South Asian (SAS) AF: 0.0574 AC: 4950 AN: 86258

European-Finnish (FIN) AF: 0.00809 AC: 432 AN: 53368

Middle Eastern (MID) AF: 0.0617 AC: 356 AN: 5768

European-Non Finnish (NFE) AF: 0.0295 AC: 32829 AN: 1112000

Other (OTH) AF: 0.0322 AC: 1944 AN: 60388

GnomAD4 genome AF: 0.0331 AC: 5039 AN: 152310 Hom.: 95 Cov.: 33 AF XY: 0.0320 AC XY: 2381 AN XY: 74488

African (AFR) AF: 0.0507 AC: 2108 AN: 41542

American (AMR) AF: 0.0179 AC: 274 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5182

South Asian (SAS) AF: 0.0590 AC: 285 AN: 4830

European-Finnish (FIN) AF: 0.00913 AC: 97 AN: 10622

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0302 AC: 2058 AN: 68038

Other (OTH) AF: 0.0331 AC: 70 AN: 2116

Alfa AF: 0.0304 Hom.: 106

Bravo AF: 0.0336

Asia WGS AF: 0.0480 AC: 167 AN: 3478

EpiCase AF: 0.0333

EpiControl AF: 0.0304

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2B (2)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy (1)
-	-	1	Distal myopathy with anterior tibial onset (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	-0.62
CADD	Benign	2.6
DANN	Benign	0.63
PhyloP100		-3.5
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35721373; hg19: chr2-71780248; COSMIC: COSV50516165;