chr2-71602794-A-G

Variant names:

• chr2-71602794-A-G
• rs121908954
• NM_001130987.2:c.3946A>G

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.3892A>G variant in DYSF, which is also known as NM_001130987.2: c.3946A>G p.(Ile1316Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1298 (p.Ile1298Val). The filtering allele frequency of the variant is 0.006916 for European (non-Finnish) genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 695/152140), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.12 and the computational predictor REVEL gives a score of 0.42. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 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/CA179991/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (46 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign reviewed by expert panel P:2 U:4 B:12 O:1
• Conservation: PhyloP100: 2.67
• Publications: 19 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.3946A>G	p.Ile1316Val	missense	Exon 36 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.3892A>G	p.Ile1298Val	missense	Exon 36 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.3943A>G	p.Ile1315Val	missense	Exon 36 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.3946A>G	p.Ile1316Val	missense	Exon 36 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.3892A>G	p.Ile1298Val	missense	Exon 36 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.3943A>G	p.Ile1315Val	missense	Exon 36 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 695 AN: 152140 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00745

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00458 AC: 1141 AN: 248942 AF XY: 0.00471

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00636

Gnomad NFE exome AF: 0.00716

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00642 AC: 9377 AN: 1461116 Hom.: 46 Cov.: 31 AF XY: 0.00636 AC XY: 4619 AN XY: 726746

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00255 AC: 114 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00146 AC: 126 AN: 86084

European-Finnish (FIN) AF: 0.00600 AC: 318 AN: 53036

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.00758 AC: 8429 AN: 1111890

Other (OTH) AF: 0.00509 AC: 307 AN: 60362

GnomAD4 genome AF: 0.00456 AC: 695 AN: 152258 Hom.: 3 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74474

African (AFR) AF: 0.00130 AC: 54 AN: 41546

American (AMR) AF: 0.00294 AC: 45 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00745 AC: 507 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00565 Hom.: 6

Bravo AF: 0.00420

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00451 AC: 547

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
1	1	2	Autosomal recessive limb-girdle muscular dystrophy type 2B (4)
-	-	3	not specified (3)
1	1	-	Miyoshi muscular dystrophy 1 (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy (1)
-	1	-	Distal myopathy with anterior tibial onset (1)
-	1	-	DYSF-related disorder (1)
-	-	1	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Benign	0.87
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.46	N
PhyloP100		2.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.41
Sift	Benign	0.35	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.46
MVP		0.53
MPC		0.12
ClinPred		0.0070	T
GERP RS		3.2
Varity_R		0.043
gMVP		0.23
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.12		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: rs121908954; hg19: chr2-71829924; COSMIC: COSV105093727; COSMIC: COSV105093727;