rs115013641

Positions:

chr2-71669705-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_001130987.2(DYSF):c.5743G>A(p.Asp1915Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,614,120 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 27 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 2.78

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 Benign. Variant got -14 ACMG points.

PM1

In a domain C2 7 (size 148) in uniprot entity DYSF_HUMAN there are 37 pathogenic changes around while only 2 benign (95%) in NM_001130987.2

BP4

Computational evidence support a benign effect (MetaRNN=0.010743886).

BP6

Variant 2-71669705-G-A is Benign according to our data. Variant chr2-71669705-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71669705-G-A is described in Lovd as [Benign]. Variant chr2-71669705-G-A is described in Lovd as [Likely_benign]. Variant chr2-71669705-G-A is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.5743G>A	p.Asp1915Asn	missense_variant	51/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.5626G>A	p.Asp1876Asn	missense_variant	50/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.5743G>A	p.Asp1915Asn	missense_variant	51/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.5626G>A	p.Asp1876Asn	missense_variant	50/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.00275

AC:

418

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00301

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00396

AC:

996

AN:

251492

Hom.:

AF XY:

0.00437

AC XY:

594

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00866

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00392

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00355

AC:

5188

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00378

AC XY:

2752

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00338

Gnomad4 ASJ exome

AF:

0.0155

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00846

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00324

Gnomad4 OTH exome

AF:

0.00429

GnomAD4 genome

AF:

0.00273

AC:

416

AN:

152236

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

206

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00767

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00301

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00397

Hom.:

Bravo

AF:

0.00306

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00390

AC:

474

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00610

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2018	This variant is associated with the following publications: (PMID: 25525159, 21522182, 17897828, 22046204, 24838345) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DYSF: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2022	Variant summary: DYSF c.5626G>A (p.Asp1876Asn) results in a conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 251492 control chromosomes, predominantly at a frequency of 0.0087 within the South Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=4) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign. -

Qualitative or quantitative defects of dysferlin

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 31, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 15, 2019

- -

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C5553104:Miyoshi myopathy

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Uncertain significance and reported on 01-23-2012 by Lab or GTR ID 1012. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

.;.;.;.;D;.;.;.;.;.;.

Eigen

Benign

0.095

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.011

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

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.4

.;.;.;.;M;.;.;.;.;.;.

MutationTaster

Benign

0.66

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.8

D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.38

Sift

Benign

0.044

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.051

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

Polyphen

0.33

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

Vest4

0.42

MVP

0.85

MPC

0.29

ClinPred

0.020

GERP RS

3.9

Varity_R

0.35

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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