rs145272777

Positions:

chr2-71667391-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001130987.2(DYSF):c.5333C>A(p.Pro1778Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,614,116 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4

Conservation

PhyloP100: -0.0560

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]

DYSF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009371072).

BP6

Variant 2-71667391-C-A is Benign according to our data. Variant chr2-71667391-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285686.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.5333C>A	p.Pro1778Gln	missense_variant	48/56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 linkuse as main transcript	c.5216C>A	p.Pro1739Gln	missense_variant	47/55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.5333C>A	p.Pro1778Gln	missense_variant	48/56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.5216C>A	p.Pro1739Gln	missense_variant	47/55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000562

AC:

141

AN:

250878

Hom.:

AF XY:

0.000604

AC XY:

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00576

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000485

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000350

AC:

511

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000378

AC XY:

275

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00524

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000219

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000355

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000653

Hom.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000519

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2020	This variant is associated with the following publications: (PMID: 30564623, 27647186) -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 10, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -

Miyoshi muscular dystrophy 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Qualitative or quantitative defects of dysferlin

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2018	The DYSF gene is the only gene in which variants are known to cause dysferlinopathy. The DYSF c.5216C>A (p.Pro1739Gln) missense variant has been reported in one study in which it is found in two siblings from a family with a history of dysferlinopathy. The variant was found in a compound heterozygous state with a deletion in one sibling and in a heterozygous state in the other (Jin et al. 2016). Both siblings were found to be negative for dysferlin expression using immunohistochemical analysis of muscle tissue (Jin et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.005924 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Pro1739Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Distal myopathy with anterior tibial onset

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

DYSF-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2019

This 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

0.096

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.42

.;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.85

D;T;T;D;D;D;D;T;T;T;D

M_CAP

Benign

0.067

MetaRNN

Benign

0.0094

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.0

.;.;.;.;L;.;.;.;.;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.1

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.066

T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.71

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0010

B;B;B;B;B;B;B;B;B;B;B

Vest4

0.40

MVP

0.70

MPC

0.14

ClinPred

0.013

GERP RS

3.3

Varity_R

0.047

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over