rs863225019

Positions:

• chr2-71526332-A-AGGACTTGCCGCAGAG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP5_Moderate

The ENST00000410020.8(DYSF):​c.1230_1231insGGGACTTGCCGCAGA​(p.Gly410_Ala411insGlyThrCysArgArg) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A411A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF ENST00000410020.8 conservative_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.121

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain C2 3 (size 136) in uniprot entity DYSF_HUMAN there are 52 pathogenic changes around while only 18 benign (74%) in ENST00000410020.8
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000410020.8.
• PP5: Variant 2-71526332-A-AGGACTTGCCGCAGAG is Pathogenic according to our data. Variant chr2-71526332-A-AGGACTTGCCGCAGAG is described in ClinVar as [Pathogenic]. Clinvar id is 217221.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.1263_1276+1dupGGACTTGCCGCAGAG		splice_donor_variant, intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.1167_1180+1dupGGACTTGCCGCAGAG		splice_donor_variant, intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.1230_1231insGGGACTTGCCGCAGA	p.Gly410_Ala411insGlyThrCysArgArg	conservative_inframe_insertion	13/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.1134_1135insGGGACTTGCCGCAGA	p.Gly378_Ala379insGlyThrCysArgArg	conservative_inframe_insertion	12/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 27, 2013

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs863225019; hg19: chr2-71753462;