chr2-71513767-C-A

Variant names:

• chr2-71513767-C-A
• rs34999029
• NM_001130987.2:c.605C>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.509C>A variant in DYSF, which is also known as NM_001130987.2: c.605C>A p.(Ala202Glu), is a missense variant predicted to cause substitution of alanine by glutamic acid at amino acid 170 (p.Ala170Glu). The filtering allele frequency of the variant is 0.01467 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 2546/251252), which is higher than the VCEP threshold of 0.003 (BA1). While this variant has been identified in individuals with LGMD (e.g., PMID:16010686, 25135358), its frequency in control populations is high relative to disease prevalence, and additional potentially causative variants were either identified as well or their presence not comprehensively ruled out (PM3 not met). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.22, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; 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; 01/08/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147766/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.0097 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (134 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: 1.39
• Publications: 29 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.605C>A	p.Ala202Glu	missense	Exon 7 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.509C>A	p.Ala170Glu	missense	Exon 6 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.602C>A	p.Ala201Glu	missense	Exon 7 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.605C>A	p.Ala202Glu	missense	Exon 7 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.509C>A	p.Ala170Glu	missense	Exon 6 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.602C>A	p.Ala201Glu	missense	Exon 7 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1472 AN: 152168 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00894

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0101 AC: 2546 AN: 251252 AF XY: 0.0102

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0124 AC: 18138 AN: 1461844 Hom.: 134 Cov.: 32 AF XY: 0.0121 AC XY: 8810 AN XY: 727216

African (AFR) AF: 0.00266 AC: 89 AN: 33478

American (AMR) AF: 0.00680 AC: 304 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 503 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00336 AC: 290 AN: 86254

European-Finnish (FIN) AF: 0.0101 AC: 541 AN: 53420

Middle Eastern (MID) AF: 0.0245 AC: 141 AN: 5750

European-Non Finnish (NFE) AF: 0.0141 AC: 15641 AN: 1111992

Other (OTH) AF: 0.0104 AC: 629 AN: 60392

GnomAD4 genome AF: 0.00966 AC: 1471 AN: 152286 Hom.: 9 Cov.: 32 AF XY: 0.00901 AC XY: 671 AN XY: 74464

African (AFR) AF: 0.00253 AC: 105 AN: 41572

American (AMR) AF: 0.0110 AC: 169 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4824

European-Finnish (FIN) AF: 0.00894 AC: 95 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0144 AC: 980 AN: 67996

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.0127 Hom.: 56

Bravo AF: 0.00943

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0153 AC: 132

ExAC AF: 0.00977 AC: 1186

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0167

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy (1)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.22
Sift	Benign	0.18	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.30
MPC		0.17
ClinPred		0.016	T
GERP RS		3.5
Varity_R		0.057
gMVP		0.19
Mutation Taster		=100/0	polymorphism

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: rs34999029; hg19: chr2-71740897;