chr2-71553135-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_001130987.2(DYSF):ā€‹c.1931T>Cā€‹(p.Met644Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,614,058 control chromosomes in the GnomAD database, including 8 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M644I) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0011 ( 0 hom., cov: 33)
Exomes š‘“: 0.0019 ( 8 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: -0.00800
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 -7 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001130987.2
BP4
Computational evidence support a benign effect (MetaRNN=0.005132675).
BP6
Variant 2-71553135-T-C is Benign according to our data. Variant chr2-71553135-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281014.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}. Variant chr2-71553135-T-C is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DYSFNM_001130987.2 linkuse as main transcriptc.1931T>C p.Met644Thr missense_variant 20/56 ENST00000410020.8
DYSFNM_003494.4 linkuse as main transcriptc.1877T>C p.Met626Thr missense_variant 20/55 ENST00000258104.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DYSFENST00000410020.8 linkuse as main transcriptc.1931T>C p.Met644Thr missense_variant 20/561 NM_001130987.2 A1O75923-13
DYSFENST00000258104.8 linkuse as main transcriptc.1877T>C p.Met626Thr missense_variant 20/551 NM_003494.4 A1O75923-1

Frequencies

GnomAD3 genomes
AF:
0.00112
AC:
170
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00216
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00128
AC:
323
AN:
251362
Hom.:
3
AF XY:
0.00130
AC XY:
176
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000491
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000416
Gnomad NFE exome
AF:
0.00252
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.00188
AC:
2751
AN:
1461742
Hom.:
8
Cov.:
34
AF XY:
0.00182
AC XY:
1324
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.000582
Gnomad4 NFE exome
AF:
0.00232
Gnomad4 OTH exome
AF:
0.00162
GnomAD4 genome
AF:
0.00112
AC:
170
AN:
152316
Hom.:
0
Cov.:
33
AF XY:
0.000913
AC XY:
68
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.00216
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00184
Hom.:
3
Bravo
AF:
0.00110
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00279
AC:
24
ExAC
AF:
0.00150
AC:
182
EpiCase
AF:
0.00174
EpiControl
AF:
0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsOct 06, 2021- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 01, 2020- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024DYSF: BP4, BS2 -
Qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Miyoshi muscular dystrophy 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsFeb 22, 2019This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 22, 2017- -
DYSF-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 10, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.052
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
3.4
DANN
Benign
0.40
DEOGEN2
Benign
0.13
.;.;.;.;T;.;.;.;.;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.054
N
LIST_S2
Benign
0.47
T;T;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.0086
T
MetaRNN
Benign
0.0051
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-1.5
.;.;N;.;N;.;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
1.2
N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.12
Sift
Benign
1.0
T;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.70
T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0
B;B;B;B;B;B;B;B;B;B;B
Vest4
0.054
MVP
0.33
MPC
0.17
ClinPred
0.00096
T
GERP RS
0.97
Varity_R
0.020
gMVP
0.17

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: rs141867897; hg19: chr2-71780265; API