rs546679270

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP6_Moderate

The ENST00000410020.8(DYSF):​c.1799G>A​(p.Arg600Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000028 in 1,604,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R600L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

DYSF
ENST00000410020.8 missense

Scores

3
5
11

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 6.97
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-71551713-G-T is described in Lovd as [Pathogenic].
BP6
Variant 2-71551713-G-A is Benign according to our data. Variant chr2-71551713-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 862087.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYSFNM_001130987.2 linkuse as main transcriptc.1799G>A p.Arg600Gln missense_variant 19/56 ENST00000410020.8 NP_001124459.1
DYSFNM_003494.4 linkuse as main transcriptc.1745G>A p.Arg582Gln missense_variant 19/55 ENST00000258104.8 NP_003485.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DYSFENST00000410020.8 linkuse as main transcriptc.1799G>A p.Arg600Gln missense_variant 19/561 NM_001130987.2 ENSP00000386881 A1O75923-13
DYSFENST00000258104.8 linkuse as main transcriptc.1745G>A p.Arg582Gln missense_variant 19/551 NM_003494.4 ENSP00000258104 A1O75923-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152122
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000558
AC:
13
AN:
232938
Hom.:
0
AF XY:
0.0000880
AC XY:
11
AN XY:
125020
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000312
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000323
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000281
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000269
AC:
39
AN:
1452444
Hom.:
0
Cov.:
31
AF XY:
0.0000374
AC XY:
27
AN XY:
721256
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000233
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000203
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152240
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.0000357
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000582
AC:
7

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Mar 11, 2020- -
Qualitative or quantitative defects of dysferlin Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 29, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.31
.;.;.;.;T;.;.;.;.;.;.
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.082
D
MetaRNN
Benign
0.39
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.048
T
MutationAssessor
Benign
1.6
.;.;L;.;L;.;.;.;.;.;.
MutationTaster
Benign
0.89
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.3
N;N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.40
Sift
Benign
0.17
T;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.45
T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.96
D;D;D;D;D;D;D;D;D;D;D
Vest4
0.63
MutPred
0.41
.;.;Loss of MoRF binding (P = 0.0258);.;Loss of MoRF binding (P = 0.0258);.;.;.;.;.;.;
MVP
0.90
MPC
0.64
ClinPred
0.54
D
GERP RS
5.5
Varity_R
0.11
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.46
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.46
Position offset: 1

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: rs546679270; hg19: chr2-71778843; API