2-71665256-A-C

Variant summary

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

The NM_001130987.2(DYSF):ā€‹c.5269A>Cā€‹(p.Thr1757Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000053 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.0610
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 (MetaRNN=0.09748086).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DYSFNM_001130987.2 linkuse as main transcriptc.5269A>C p.Thr1757Pro missense_variant 47/56 ENST00000410020.8
DYSFNM_003494.4 linkuse as main transcriptc.5152A>C p.Thr1718Pro missense_variant 46/55 ENST00000258104.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DYSFENST00000410020.8 linkuse as main transcriptc.5269A>C p.Thr1757Pro missense_variant 47/561 NM_001130987.2 A1O75923-13
DYSFENST00000258104.8 linkuse as main transcriptc.5152A>C p.Thr1718Pro missense_variant 46/551 NM_003494.4 A1O75923-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251470
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000527
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000527
AC:
77
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.0000523
AC XY:
38
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000674
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000285
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJan 03, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 23, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 15, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24438169) -
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jan 11, 2021- -
Uncertain significance, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 24, 2023- -
Qualitative or quantitative defects of dysferlin Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeApr 12, 2022This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1718 of the DYSF protein (p.Thr1718Pro). This variant is present in population databases (rs746919714, gnomAD 0.005%). 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: 290354). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DYSF protein function. 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
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
15
DANN
Benign
0.85
DEOGEN2
Benign
0.16
.;.;.;.;T;.;.;.;.;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.056
N
LIST_S2
Benign
0.71
T;T;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.097
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
-0.34
.;.;.;.;N;.;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.87
N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.20
Sift
Benign
0.15
T;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.29
T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.021
B;B;B;B;B;B;B;B;B;B;B
Vest4
0.18
MutPred
0.49
.;.;.;.;Loss of stability (P = 0.0322);.;.;.;.;.;.;
MVP
0.53
MPC
0.19
ClinPred
0.043
T
GERP RS
1.3
Varity_R
0.081
gMVP
0.57

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: rs746919714; hg19: chr2-71892386; API