chr2-71660585-T-C

Variant names:

• chr2-71660585-T-C
• rs146384562
• NM_001130987.2:c.4937T>C

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.4820T>C variant in DYSF, which is also known as NM_001130987.2: c.4937T>C p.(Ile1646Thr), is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 1607 (p.Ile1607Thr). The filtering allele frequency of the variant is 0.01198 for South Asian exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 742/251478), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.19 and the computational predictor REVEL gives a score of 0.36. 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/CA275275/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.0017 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (24 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:13
• Conservation: PhyloP100: 5.13
• Publications: 8 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.4937T>C	p.Ile1646Thr	missense	Exon 45 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.4820T>C	p.Ile1607Thr	missense	Exon 44 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.4934T>C	p.Ile1645Thr	missense	Exon 45 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.4937T>C	p.Ile1646Thr	missense	Exon 45 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4820T>C	p.Ile1607Thr	missense	Exon 44 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.4934T>C	p.Ile1645Thr	missense	Exon 45 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 152188 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00295 AC: 742 AN: 251478 AF XY: 0.00342

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00206 AC: 3005 AN: 1461642 Hom.: 24 Cov.: 31 AF XY: 0.00239 AC XY: 1736 AN XY: 727138

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.00103 AC: 46 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26130

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

South Asian (SAS) AF: 0.0136 AC: 1169 AN: 86252

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53400

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5764

European-Non Finnish (NFE) AF: 0.00133 AC: 1479 AN: 1111832

Other (OTH) AF: 0.00248 AC: 150 AN: 60374

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152306 Hom.: 3 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74484

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.00372 AC: 57 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

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

South Asian (SAS) AF: 0.0151 AC: 73 AN: 4820

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68020

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00199 Hom.: 2

Bravo AF: 0.00131

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00334 AC: 405

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00225

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.055
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.1
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.038	D
Polyphen		0.0	B
Vest4		0.62
MVP		0.76
MPC		0.21
ClinPred		0.047	T
GERP RS		5.8
Varity_R		0.32
gMVP		0.61
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs146384562; hg19: chr2-71887715; COSMIC: COSV106087139;