rs7573406

Variant names:

• chr2-71644058-C-T
• rs7573406
• NM_001130987.2:c.4621C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-71644058-C-T
• chr2-71644058-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001130987.2(DYSF):​c.4621C>T​(p.Leu1541Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00823 in 1,609,458 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene DYSF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0081 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (83 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign reviewed by expert panel U:3 B:11
• Conservation: PhyloP100: 1.23
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-71644058-C-T is Benign according to our data. Variant chr2-71644058-C-T is described in ClinVar as Benign. ClinVar VariationId is 94325.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00815 (1241/152292) while in subpopulation SAS AF = 0.0145 (70/4826). AF 95% confidence interval is 0.0118. There are 7 homozygotes in GnomAd4. There are 584 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.4621C>T	p.Leu1541Leu	synonymous	Exon 42 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.4504C>T	p.Leu1502Leu	synonymous	Exon 41 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.4618C>T	p.Leu1540Leu	synonymous	Exon 42 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.4621C>T	p.Leu1541Leu	synonymous	Exon 42 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4504C>T	p.Leu1502Leu	synonymous	Exon 41 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.4618C>T	p.Leu1540Leu	synonymous	Exon 42 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1237 AN: 152174 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00794

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00908

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00791 AC: 1919 AN: 242576 AF XY: 0.00878

Gnomad AFR exome AF: 0.00751

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.00247

Gnomad NFE exome AF: 0.00812

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.00824 AC: 12006 AN: 1457166 Hom.: 83 Cov.: 32 AF XY: 0.00865 AC XY: 6262 AN XY: 724268

African (AFR) AF: 0.00775 AC: 259 AN: 33440

American (AMR) AF: 0.00687 AC: 304 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.00959 AC: 249 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0170 AC: 1447 AN: 85088

European-Finnish (FIN) AF: 0.00354 AC: 188 AN: 53172

Middle Eastern (MID) AF: 0.0328 AC: 188 AN: 5728

European-Non Finnish (NFE) AF: 0.00788 AC: 8746 AN: 1109640

Other (OTH) AF: 0.0104 AC: 625 AN: 60244

GnomAD4 genome AF: 0.00815 AC: 1241 AN: 152292 Hom.: 7 Cov.: 33 AF XY: 0.00784 AC XY: 584 AN XY: 74482

African (AFR) AF: 0.00799 AC: 332 AN: 41546

American (AMR) AF: 0.00883 AC: 135 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4826

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00908 AC: 618 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00892 Hom.: 4

Bravo AF: 0.00868

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.2
DANN	Benign	0.50
PhyloP100		1.2
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs7573406; hg19: chr2-71871188; COSMIC: COSV50435908; COSMIC: COSV50435908;