NM_001130987.2:c.3119G>A

Variant names:

• chr2-71570632-G-A
• rs34211915
• NM_001130987.2:c.3119G>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.3065G>A variant in DYSF, which is also known as NM_001130987.2: c.3119G>A p.(Arg1040Gln), is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1022 (p.Arg1022Gln). The filtering allele frequency of the variant is 0.03338 for African/African American genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 3745/152196), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.02, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.39, 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/CA147743/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.025 (57 hom., cov: 33)
  • Exomes 𝑓: 0.021 (389 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: 4.75
• Publications: 16 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.3119G>A	p.Arg1040Gln	missense	Exon 29 of 56	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.3065G>A	p.Arg1022Gln	missense	Exon 29 of 55	NP_003485.1
	DYSF	NM_001130981.2		c.3116G>A	p.Arg1039Gln	missense	Exon 29 of 56	NP_001124453.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.3119G>A	p.Arg1040Gln	missense	Exon 29 of 56	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.3065G>A	p.Arg1022Gln	missense	Exon 29 of 55	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.3116G>A	p.Arg1039Gln	missense	Exon 29 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3745 AN: 152196 Hom.: 57 Cov.: 33

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0243

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0184 AC: 4611 AN: 250548 AF XY: 0.0177

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00786

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0249

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0209 AC: 30594 AN: 1461746 Hom.: 389 Cov.: 33 AF XY: 0.0200 AC XY: 14576 AN XY: 727176

African (AFR) AF: 0.0351 AC: 1176 AN: 33480

American (AMR) AF: 0.0104 AC: 464 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00723 AC: 189 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86254

European-Finnish (FIN) AF: 0.0352 AC: 1879 AN: 53392

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.0232 AC: 25782 AN: 1111950

Other (OTH) AF: 0.0174 AC: 1053 AN: 60378

GnomAD4 genome AF: 0.0246 AC: 3746 AN: 152310 Hom.: 57 Cov.: 33 AF XY: 0.0245 AC XY: 1826 AN XY: 74472

African (AFR) AF: 0.0348 AC: 1447 AN: 41552

American (AMR) AF: 0.0119 AC: 182 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0385 AC: 409 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0243 AC: 1650 AN: 68020

Other (OTH) AF: 0.0152 AC: 32 AN: 2110

Alfa AF: 0.0227 Hom.: 156

Bravo AF: 0.0226

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.0332 AC: 146

ESP6500EA AF: 0.0187 AC: 161

ExAC AF: 0.0199 AC: 2414

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0199

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	2	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.39
Sift	Benign	0.59	T
Sift4G	Benign	0.58	T
Polyphen		0.17	B
Vest4		0.61
MPC		0.18
ClinPred		0.022	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.53
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34211915; hg19: chr2-71797762; COSMIC: COSV50313285;