rs149875093

chr2-71520250-CT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001130987.2(DYSF):c.1033+43del 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 (★★).

• 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

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 Benign. Variant got -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 id is 259088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71520250-CT-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.1033+43del		intron_variant		ENST00000410020.8
DYSF	NM_003494.4	c.937+43del		intron_variant		ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.937+43del		intron_variant		1	NM_003494.4	A1
DYSF	ENST00000410020.8	c.1033+43del		intron_variant		1	NM_001130987.2	A1

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

GnomAD3 exomes AF: 0.0349 AC: 8774 AN: 251478 Hom.: 188 AF XY: 0.0359 AC XY: 4882 AN XY: 135914

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 SAS exome AF: 0.0345

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

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.0210

Gnomad4 ASJ exome AF: 0.0887

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0362

Gnomad4 FIN exome AF: 0.0183

Gnomad4 NFE exome AF: 0.0514

Gnomad4 OTH exome AF: 0.0495

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

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.0873

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0350

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.0478

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0248 Hom.: 17

Bravo AF: 0.0366

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs149875093; hg19: chr2-71747380;