rs1553416039

Positions:

• chr2-71669611-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001130987.2(DYSF):​c.5650del​(p.Ile1884LeufsTer121) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DYSF NM_001130987.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.275

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-71669611-GA-G is Pathogenic according to our data. Variant chr2-71669611-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71669611-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.5650del	p.Ile1884LeufsTer121	frameshift_variant	51/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.5533del	p.Ile1845LeufsTer121	frameshift_variant	50/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.5650del	p.Ile1884LeufsTer121	frameshift_variant	51/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.5533del	p.Ile1845LeufsTer121	frameshift_variant	50/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 07, 2017

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 07, 2018

The p.Ile1884LeufsX121 variant in DYSF has not been reported in affected individ uals or large population studies. This variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 1884 and leads to a premature termination codon 121 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein. Biallelic loss o f function of the DYSF gene has been associated with limb-girdle muscular dystro phy type 2B or Miyoshi myopathy (dysferlinopathies). In summary, although additi onal studies are required to fully establish its clinical significance, the p.Il e1884LeufsX121 variant in DYSF is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553416039; hg19: chr2-71896741;