rs34836829

chr2-71568330-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001130987.2(DYSF):c.2856G>A(p.Pro952=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,614,078 control chromosomes in the GnomAD database, including 1,366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (88 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1278 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.77

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-71568330-G-A is Benign according to our data. Variant chr2-71568330-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71568330-G-A is described in Lovd as [Benign]. Variant chr2-71568330-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3825/152286) while in subpopulation NFE AF= 0.0385 (2616/68018). AF 95% confidence interval is 0.0372. There are 88 homozygotes in gnomad4. There are 1797 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 88 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.2856G>A	p.Pro952=	synonymous_variant	26/56	ENST00000410020.8
DYSF	NM_003494.4	c.2802G>A	p.Pro934=	synonymous_variant	26/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.2856G>A	p.Pro952=	synonymous_variant	26/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.2802G>A	p.Pro934=	synonymous_variant	26/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3826 AN: 152168 Hom.: 88 Cov.: 33

Gnomad AFR AF: 0.00663

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0278 AC: 6968 AN: 250236 Hom.: 138 AF XY: 0.0294 AC XY: 3973 AN XY: 135346

Gnomad AFR exome AF: 0.00573

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0667

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0365

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0367

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0386 AC: 56414 AN: 1461792 Hom.: 1278 Cov.: 36 AF XY: 0.0385 AC XY: 28007 AN XY: 727194

Gnomad4 AFR exome AF: 0.00541

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0684

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0379

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0425

Gnomad4 OTH exome AF: 0.0387

GnomAD4 genome AF: 0.0251 AC: 3825 AN: 152286 Hom.: 88 Cov.: 33 AF XY: 0.0241 AC XY: 1797 AN XY: 74464

Gnomad4 AFR AF: 0.00661

Gnomad4 AMR AF: 0.0182

Gnomad4 ASJ AF: 0.0622

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0348

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.0385

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0348 Hom.: 70

Bravo AF: 0.0244

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Pro952Pro in exon 26 of DYSF: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 4.3% (370/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34836829). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2016	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. -

Qualitative or quantitative defects of dysferlin Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.59
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs34836829; hg19: chr2-71795460; COSMIC: COSV50309232; COSMIC: COSV50309232;