rs34671418

Variant names:

• chr2-71564202-A-G
• rs34671418
• NM_001130987.2:c.2554A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.2500A>G variant in DYSF, which is also known as NM_001130987.2: c.2554A>G p.(Ile852Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 834 (p.Ile834Val). The filtering allele frequency of the variant is 0.08367 for African/African American genome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 1541/31380), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0, which suggests it does not impact splicing and is below the LGMD VCEP threshold of ≤0.05. The computational predictor REVEL gives a score of 0.08, which is below the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1) (BP4). 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, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147734/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.041 (191 hom., cov: 33)
  • Exomes 𝑓: 0.024 (575 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: 2.92
• Publications: 13 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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• 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.2554A>G	p.Ile852Val	missense	Exon 24 of 56	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.2500A>G	p.Ile834Val	missense	Exon 24 of 55	NP_003485.1
	DYSF	NM_001130981.2		c.2551A>G	p.Ile851Val	missense	Exon 24 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.2554A>G	p.Ile852Val	missense	Exon 24 of 56	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.2500A>G	p.Ile834Val	missense	Exon 24 of 55	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.2551A>G	p.Ile851Val	missense	Exon 24 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6172 AN: 152184 Hom.: 190 Cov.: 33

Gnomad AFR AF: 0.0852

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0232 AC: 5833 AN: 251470 AF XY: 0.0216

Gnomad AFR exome AF: 0.0855

Gnomad AMR exome AF: 0.00948

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.0241 AC: 35283 AN: 1461878 Hom.: 575 Cov.: 32 AF XY: 0.0232 AC XY: 16867 AN XY: 727242

African (AFR) AF: 0.0882 AC: 2953 AN: 33480

American (AMR) AF: 0.0106 AC: 476 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 687 AN: 26136

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

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.0325 AC: 1734 AN: 53416

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.0251 AC: 27922 AN: 1112000

Other (OTH) AF: 0.0235 AC: 1421 AN: 60396

GnomAD4 genome AF: 0.0407 AC: 6198 AN: 152302 Hom.: 191 Cov.: 33 AF XY: 0.0401 AC XY: 2985 AN XY: 74470

African (AFR) AF: 0.0856 AC: 3555 AN: 41554

American (AMR) AF: 0.0184 AC: 281 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0364 AC: 387 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0272 AC: 1849 AN: 68014

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.0298 Hom.: 253

Bravo AF: 0.0400

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.0819 AC: 361

ESP6500EA AF: 0.0230 AC: 198

ExAC AF: 0.0258 AC: 3132

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0242

EpiControl AF: 0.0216

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Miyoshi myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N
PhyloP100		2.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.077
Sift	Benign	0.26	T
Sift4G	Benign	0.35	T
Polyphen		0.050	B
Vest4		0.21
MPC		0.13
ClinPred		0.0065	T
GERP RS		2.4
Varity_R		0.033
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs34671418; hg19: chr2-71791332; COSMIC: COSV50335266;