2-71511847-G-A

Variant names:

• chr2-71511847-G-A
• rs34997054
• NM_001130987.2:c.386G>A

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.383G>A variant in DYSF, which is also known as NM_001130987.2: c.386G>A p.(Gly129Glu), is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 128, p.(Gly128Glu). The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.03324 (the lower threshold of the 95% CI of 223/5988 Middle Eastern chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). While this variant has been reported with a second heterozygous DYSF variant in an individual with reduced dysferlin expression (PMID:21522182), its frequency in control populations is high relative to disease prevalence (PM3 not met). The SpliceAI score for this variant is 0.01, suggesting it does not impact splicing. The computational predictor REVEL gives a score of 0.45 (PP3 and BP4 not met). 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/CA147747/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.0041 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (89 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:19
• Conservation: PhyloP100: 8.15
• Publications: 12 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 -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.386G>A	p.Gly129Glu	missense	Exon 5 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.383G>A	p.Gly128Glu	missense	Exon 5 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.383G>A	p.Gly128Glu	missense	Exon 5 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.386G>A	p.Gly129Glu	missense	Exon 5 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.383G>A	p.Gly128Glu	missense	Exon 5 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.383G>A	p.Gly128Glu	missense	Exon 5 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 633 AN: 152220 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00403

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00713 AC: 1118 AN: 156748 AF XY: 0.00750

Gnomad AFR exome AF: 0.000571

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.0598

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000965

Gnomad NFE exome AF: 0.00491

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00468 AC: 6545 AN: 1399374 Hom.: 89 Cov.: 31 AF XY: 0.00485 AC XY: 3348 AN XY: 690198

African (AFR) AF: 0.00212 AC: 67 AN: 31596

American (AMR) AF: 0.00521 AC: 186 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.0593 AC: 1493 AN: 25180

East Asian (EAS) AF: 0.0000839 AC: 3 AN: 35738

South Asian (SAS) AF: 0.00413 AC: 327 AN: 79234

European-Finnish (FIN) AF: 0.00108 AC: 53 AN: 49242

Middle Eastern (MID) AF: 0.0374 AC: 213 AN: 5694

European-Non Finnish (NFE) AF: 0.00346 AC: 3736 AN: 1078976

Other (OTH) AF: 0.00805 AC: 467 AN: 58008

GnomAD4 genome AF: 0.00414 AC: 631 AN: 152338 Hom.: 9 Cov.: 33 AF XY: 0.00419 AC XY: 312 AN XY: 74494

African (AFR) AF: 0.00111 AC: 46 AN: 41582

American (AMR) AF: 0.00340 AC: 52 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3470

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

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4832

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10630

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00400 AC: 272 AN: 68014

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00509 Hom.: 21

Bravo AF: 0.00433

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000508 AC: 2

ESP6500EA AF: 0.00422 AC: 32

ExAC AF: 0.00404 AC: 251

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	Autosomal recessive limb-girdle muscular dystrophy type 2B (5)
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy (2)
-	-	1	DYSF-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Miyoshi muscular dystrophy 1 (1)
1	-	-	Muscular dystrophy (1)
-	-	1	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0076	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.70
MVP		0.85
MPC		0.40
ClinPred		0.013	T
GERP RS		4.5
Varity_R		0.43
gMVP		0.42
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs34997054; hg19: chr2-71738977; COSMIC: COSV105093661;