rs149875093

Variant names:

• chr2-71520250-CT-C
• rs149875093
• NM_001130987.2:c.1033+43delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001130987.2(DYSF):​c.1033+43delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 1,612,022 control chromosomes in the GnomAD database, including 1,994 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). The gene DYSF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.036 (124 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1870 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.204
• Publications: 1 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-71520250-CT-C is Benign according to our data. Variant chr2-71520250-CT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 259088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

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.1033+43delT		intron	N/A	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.937+43delT		intron	N/A	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.1030+43delT		intron	N/A	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.1033+43delT		intron	N/A	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.937+43delT		intron	N/A	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.1030+43delT		intron	N/A	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0362 AC: 5516 AN: 152172 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0349 AC: 8774 AN: 251478 AF XY: 0.0359

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.0196

Gnomad ASJ exome AF: 0.0861

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.0454

Gnomad OTH exome AF: 0.0396

GnomAD4 exome AF: 0.0468 AC: 68387 AN: 1459734 Hom.: 1870 Cov.: 32 AF XY: 0.0464 AC XY: 33679 AN XY: 726390

African (AFR) AF: 0.0204 AC: 681 AN: 33430

American (AMR) AF: 0.0210 AC: 939 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0887 AC: 2318 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0362 AC: 3125 AN: 86214

European-Finnish (FIN) AF: 0.0183 AC: 979 AN: 53410

Middle Eastern (MID) AF: 0.0467 AC: 269 AN: 5762

European-Non Finnish (NFE) AF: 0.0514 AC: 57086 AN: 1110042

Other (OTH) AF: 0.0495 AC: 2989 AN: 60336

GnomAD4 genome AF: 0.0363 AC: 5522 AN: 152288 Hom.: 124 Cov.: 32 AF XY: 0.0342 AC XY: 2544 AN XY: 74448

African (AFR) AF: 0.0239 AC: 994 AN: 41556

American (AMR) AF: 0.0325 AC: 497 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 303 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0350 AC: 169 AN: 4822

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10614

Middle Eastern (MID) AF: 0.0552 AC: 16 AN: 290

European-Non Finnish (NFE) AF: 0.0478 AC: 3254 AN: 68020

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.0248 Hom.: 17

Bravo AF: 0.0366

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs149875093; hg19: chr2-71747380;