NM_001130987.2:c.2020A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B.

-6

PP3BP4_ModerateBS1_SupportingBS2

The NM_001130987.2(DYSF):c.2020A>G(p.Lys674Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000699 in 1,581,850 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00072 ( 4 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:2

Conservation

PhyloP100: 9.31

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuromuscular disease caused by qualitative or quantitative defects of dysferlin
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
autosomal recessive limb-girdle muscular dystrophy type 2B
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
distal myopathy with anterior tibial onset
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital myopathy, Paradas type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Miyoshi myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYSF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.15630594).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000715 (1025/1432870) while in subpopulation SAS AF = 0.00185 (159/85920). AF 95% confidence interval is 0.00162. There are 4 homozygotes in GnomAdExome4. There are 541 alleles in the male GnomAdExome4 subpopulation. Median coverage is 39. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.2020A>G	p.Lys674Glu	missense_variant	Exon 21 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.1966A>G	p.Lys656Glu	missense_variant	Exon 21 of 55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.2020A>G	p.Lys674Glu	missense_variant	Exon 21 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.1966A>G	p.Lys656Glu	missense_variant	Exon 21 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.000537

AC:

AN:

148878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000135

Gnomad ASJ

AF:

0.00406

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00198

Gnomad FIN

AF:

0.00129

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000594

Gnomad OTH

AF:

0.000487

GnomAD2 exomes

AF:

0.000816

AC:

205

AN:

251164

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.000687

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000715

AC:

1025

AN:

1432870

Hom.:

Cov.:

AF XY:

0.000759

AC XY:

541

AN XY:

712822

show subpopulations

African (AFR)

AF:

0.0000612

AC:

AN:

32676

American (AMR)

AF:

0.000274

AC:

AN:

43832

Ashkenazi Jewish (ASJ)

AF:

0.00300

AC:

AN:

25016

East Asian (EAS)

AF:

0.0000269

AC:

AN:

37126

South Asian (SAS)

AF:

0.00185

AC:

159

AN:

85920

European-Finnish (FIN)

AF:

0.000981

AC:

AN:

50966

Middle Eastern (MID)

AF:

0.00179

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.000616

AC:

673

AN:

1093284

Other (OTH)

AF:

0.000736

AC:

AN:

58454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000544

AC:

AN:

148980

Hom.:

Cov.:

AF XY:

0.000661

AC XY:

AN XY:

72566

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40646

American (AMR)

AF:

0.000134

AC:

AN:

14872

Ashkenazi Jewish (ASJ)

AF:

0.00406

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

4780

South Asian (SAS)

AF:

0.00220

AC:

AN:

4548

European-Finnish (FIN)

AF:

0.00129

AC:

AN:

10046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000594

AC:

AN:

67378

Other (OTH)

AF:

0.000482

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000691

Hom.:

Bravo

AF:

0.000404

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000848

AC:

103

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Dec 06, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in published literature (Pavoni et al., 2011) as 1966 A>G; K656Q,due to the use of alternate nomenclature, in individual with Miyoshi myopathy who also harbored the c.2200_2205delinsT; the phase of these variants is unknown; This variant is associated with the following publications: (PMID: 22046204, 21522182) -

Sep 19, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 03, 2021

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 04, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Limb-girdle muscular dystrophy, recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Distal myopathy with anterior tibial onset

Uncertain:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DYSF-related disorder

Uncertain:1

Mar 21, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DYSF c.1966A>G variant is predicted to result in the amino acid substitution p.Lys656Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.31% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including 1 homozygote (http://gnomad.broadinstitute.org/variant/2-71780972-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Miyoshi muscular dystrophy 1

Uncertain:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Miyoshi myopathy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

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

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.16

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

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.8

.;.;H;.;H;.;.;.;.;.;.

PhyloP100

9.3

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.6

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

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.99

D;D;D;P;P;P;P;D;P;D;D

Vest4

0.91

MVP

0.86

MPC

0.74

ClinPred

0.20

GERP RS

3.7

Varity_R

0.66

gMVP

0.89

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over