rs143762717

Variant names:

• chr2-71682530-G-A
• rs143762717
• NM_001130987.2:c.6174G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001130987.2(DYSF):​c.6174G>A​(p.Arg2058Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene DYSF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (1 hom.)
• Consequence: DYSF NM_001130987.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:7
• Conservation: PhyloP100: 1.84
• Publications: 2 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

Specifications for DYSF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-71682530-G-A is Benign according to our data. Variant chr2-71682530-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197967.

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.6174G>A	p.Arg2058Arg	splice_region synonymous	Exon 55 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.6057G>A	p.Arg2019Arg	splice_region synonymous	Exon 54 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.6171G>A	p.Arg2057Arg	splice_region synonymous	Exon 55 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.6174G>A	p.Arg2058Arg	splice_region synonymous	Exon 55 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.6057G>A	p.Arg2019Arg	splice_region synonymous	Exon 54 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.6171G>A	p.Arg2057Arg	splice_region synonymous	Exon 55 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000485 AC: 122 AN: 251478 AF XY: 0.000515

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000934 AC: 1365 AN: 1461886 Hom.: 1 Cov.: 31 AF XY: 0.000903 AC XY: 657 AN XY: 727246

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26136

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00112 AC: 1247 AN: 1112008

Other (OTH) AF: 0.00139 AC: 84 AN: 60396

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74402

African (AFR) AF: 0.000120 AC: 5 AN: 41526

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000868 AC: 59 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000992 Hom.: 0

Bravo AF: 0.000544

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	not provided (6)
-	1	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (2)
-	1	1	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	1	DYSF-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Miyoshi myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		1.8
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.090		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: rs143762717; hg19: chr2-71909660;