rs11558179

Variant names:

• chr2-71611313-C-T
• rs11558179
• NM_001130987.2:c.4026C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001130987.2(DYSF):​c.4026C>T​(p.Asn1342Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 1,613,634 control chromosomes in the GnomAD database, including 11,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (5026 hom., cov: 32)
  • Exomes 𝑓: 0.065 (6594 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.313
• Publications: 9 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-71611313-C-T is Benign according to our data. Variant chr2-71611313-C-T is described in ClinVar as Benign. ClinVar VariationId is 94314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.313 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 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.4026C>T	p.Asn1342Asn	synonymous	Exon 37 of 56	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.3972C>T	p.Asn1324Asn	synonymous	Exon 37 of 55	NP_003485.1
	DYSF	NM_001130981.2		c.4023C>T	p.Asn1341Asn	synonymous	Exon 37 of 56	NP_001124453.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.4026C>T	p.Asn1342Asn	synonymous	Exon 37 of 56	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.3972C>T	p.Asn1324Asn	synonymous	Exon 37 of 55	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.4023C>T	p.Asn1341Asn	synonymous	Exon 37 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26729 AN: 152024 Hom.: 5006 Cov.: 32

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0755

Gnomad EAS AF: 0.0384

Gnomad SAS AF: 0.0551

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.0867 AC: 21738 AN: 250610 AF XY: 0.0772

Gnomad AFR exome AF: 0.490

Gnomad AMR exome AF: 0.0933

Gnomad ASJ exome AF: 0.0830

Gnomad EAS exome AF: 0.0365

Gnomad FIN exome AF: 0.0435

Gnomad NFE exome AF: 0.0531

Gnomad OTH exome AF: 0.0792

GnomAD4 exome AF: 0.0647 AC: 94597 AN: 1461492 Hom.: 6594 Cov.: 33 AF XY: 0.0625 AC XY: 45436 AN XY: 727028

African (AFR) AF: 0.493 AC: 16491 AN: 33474

American (AMR) AF: 0.0942 AC: 4210 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0846 AC: 2211 AN: 26128

East Asian (EAS) AF: 0.0469 AC: 1862 AN: 39700

South Asian (SAS) AF: 0.0537 AC: 4634 AN: 86250

European-Finnish (FIN) AF: 0.0485 AC: 2589 AN: 53396

Middle Eastern (MID) AF: 0.0832 AC: 480 AN: 5768

European-Non Finnish (NFE) AF: 0.0515 AC: 57216 AN: 1111718

Other (OTH) AF: 0.0812 AC: 4904 AN: 60368

GnomAD4 genome AF: 0.176 AC: 26796 AN: 152142 Hom.: 5026 Cov.: 32 AF XY: 0.173 AC XY: 12870 AN XY: 74388

African (AFR) AF: 0.478 AC: 19806 AN: 41448

American (AMR) AF: 0.117 AC: 1790 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 262 AN: 3472

East Asian (EAS) AF: 0.0383 AC: 198 AN: 5166

South Asian (SAS) AF: 0.0545 AC: 263 AN: 4826

European-Finnish (FIN) AF: 0.0455 AC: 483 AN: 10618

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0531 AC: 3608 AN: 67998

Other (OTH) AF: 0.137 AC: 289 AN: 2108

Alfa AF: 0.0850 Hom.: 4397

Bravo AF: 0.194

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.0547

EpiControl AF: 0.0533

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Miyoshi muscular dystrophy 1 (1)
-	-	1	Miyoshi myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.2
DANN	Benign	0.85
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs11558179; hg19: chr2-71838443; COSMIC: COSV50651151;