2-71526286-G-C

Variant names:

• chr2-71526286-G-C
• rs150724610
• NM_001130987.2:c.1216G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP2

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1120G>C variant in DYSF, which is also known as NM_001130987.2: c.1216G>C p.(Val406Leu), is a missense variant predicted to cause substitution of valine by leucine at amino acid 374 (p.Val374Leu). The filtering allele frequency of the variant is 0.009514 for European (non-Finnish) genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 926/152226), which is higher than the VCEP threshold of 0.003 (BA1). This variant has also been observed in cis with the variant c.610C>T p.(Arg204Ter), which is classified as pathogenic by the ClinGen LGMD VCEP (PMID:25135358) (BP2). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.21, 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, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147717/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (75 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 3.15
• Publications: 23 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 -9 ACMG points.

• BP2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.1216G>C	p.Val406Leu	missense	Exon 13 of 56	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.1120G>C	p.Val374Leu	missense	Exon 12 of 55	NP_003485.1
	DYSF	NM_001130981.2		c.1213G>C	p.Val405Leu	missense	Exon 13 of 56	NP_001124453.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.1216G>C	p.Val406Leu	missense	Exon 13 of 56	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1120G>C	p.Val374Leu	missense	Exon 12 of 55	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.1213G>C	p.Val405Leu	missense	Exon 13 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 926 AN: 152226 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00549 AC: 1380 AN: 251414 AF XY: 0.00565

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.00869

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00852 AC: 12454 AN: 1461884 Hom.: 75 Cov.: 32 AF XY: 0.00832 AC XY: 6048 AN XY: 727244

African (AFR) AF: 0.00122 AC: 41 AN: 33478

American (AMR) AF: 0.00203 AC: 91 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00245 AC: 211 AN: 86258

European-Finnish (FIN) AF: 0.00781 AC: 417 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0101 AC: 11277 AN: 1112006

Other (OTH) AF: 0.00676 AC: 408 AN: 60396

GnomAD4 genome AF: 0.00608 AC: 926 AN: 152344 Hom.: 6 Cov.: 33 AF XY: 0.00546 AC XY: 407 AN XY: 74488

African (AFR) AF: 0.00142 AC: 59 AN: 41592

American (AMR) AF: 0.00398 AC: 61 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00848 AC: 90 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0101 AC: 690 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00578

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.00567 AC: 688

EpiCase AF: 0.00971

EpiControl AF: 0.00954

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Sep 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYSF: BP4, BS1, BS2

May 08, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Jun 16, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

May 20, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:2

Jan 12, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 21, 2017

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Autosomal recessive limb-girdle muscular dystrophy Benign:1

Jan 08, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_003494.4: c.1120G>C variant in DYSF, which is also known as NM_001130987.2: c.1216G>C p.(Val406Leu), is a missense variant predicted to cause substitution of valine by leucine at amino acid 374 (p.Val374Leu). The filtering allele frequency of the variant is 0.009514 for European (non-Finnish) genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 926/152226), which is higher than the VCEP threshold of 0.003 (BA1). This variant has also been observed in cis with the variant c.610C>T p.(Arg204Ter), which is classified as pathogenic by the ClinGen LGMD VCEP (PMID: 25135358) (BP2). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.21, 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, BP2.

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.97	L
PhyloP100		3.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.21
Sift	Benign	0.089	T
Sift4G	Benign	0.092	T
Polyphen		0.0020	B
Vest4		0.15
MutPred		0.72		Gain of disorder (P = 0.1116)
MVP		0.64
MPC		0.16
ClinPred		0.0065	T
GERP RS		2.2
Varity_R		0.072
gMVP		0.36
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: rs150724610; hg19: chr2-71753416;