2-71553929-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001130987.2(DYSF):​c.2107C>T​(p.Leu703Leu) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

DYSF
NM_001130987.2 splice_region, synonymous

Scores

2
Splicing: ADA: 0.003222
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.18
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.29).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYSFNM_001130987.2 linkc.2107C>T p.Leu703Leu splice_region_variant, synonymous_variant 21/56 ENST00000410020.8 NP_001124459.1 O75923-13
DYSFNM_003494.4 linkc.2053C>T p.Leu685Leu splice_region_variant, synonymous_variant 21/55 ENST00000258104.8 NP_003485.1 O75923-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DYSFENST00000410020.8 linkc.2107C>T p.Leu703Leu splice_region_variant, synonymous_variant 21/561 NM_001130987.2 ENSP00000386881.3 O75923-13
DYSFENST00000258104.8 linkc.2053C>T p.Leu685Leu splice_region_variant, synonymous_variant 21/551 NM_003494.4 ENSP00000258104.3 O75923-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
38
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Qualitative or quantitative defects of dysferlin Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 17, 2022Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This sequence change affects codon 685 of the DYSF mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DYSF protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 1474516). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.29
CADD
Benign
18
DANN
Benign
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0032
dbscSNV1_RF
Benign
0.072
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.26
Position offset: -2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-71781059; API