rs34836829

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -4.77
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 88 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DYSFNM_001130987.2 linkuse as main transcriptc.2856G>A p.Pro952= synonymous_variant 26/56 ENST00000410020.8
DYSFNM_003494.4 linkuse as main transcriptc.2802G>A p.Pro934= synonymous_variant 26/55 ENST00000258104.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DYSFENST00000410020.8 linkuse as main transcriptc.2856G>A p.Pro952= synonymous_variant 26/561 NM_001130987.2 A1O75923-13
DYSFENST00000258104.8 linkuse as main transcriptc.2802G>A p.Pro934= synonymous_variant 26/551 NM_003494.4 A1O75923-1

Frequencies

GnomAD3 genomes
AF:
0.0251
AC:
3826
AN:
152168
Hom.:
88
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 13, 2015p.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 submitterclinical testingEurofins Ntd Llc (ga)Nov 22, 2013- -
Likely benign, no assertion criteria providedclinical testingGenetic 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 submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 10, 2016This 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 submitterclinical testingInvitaeFeb 01, 2024- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
Benign, no assertion criteria providedclinical testingNatera, 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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