2-71674156-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001130987.2(DYSF):c.5785-41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 1,591,058 control chromosomes in the GnomAD database, including 558,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 46340 hom., cov: 31)

Exomes 𝑓: 0.84 ( 512354 hom. )

Consequence

DYSF
NM_001130987.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.675

Publications

12 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 2-71674156-C-T is Benign according to our data. Variant chr2-71674156-C-T is described in ClinVar as Benign. ClinVar VariationId is 259082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.5785-41C>T		intron_variant	Intron 51 of 55	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 link	c.5668-41C>T		intron_variant	Intron 50 of 54	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.5785-41C>T		intron_variant	Intron 51 of 55	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8 link	c.5668-41C>T		intron_variant	Intron 50 of 54	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes

AF:

0.773

AC:

117510

AN:

151952

Hom.:

46341

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

Gnomad AMI

AF:

0.830

Gnomad AMR

AF:

0.766

Gnomad ASJ

AF:

0.792

Gnomad EAS

AF:

0.699

Gnomad SAS

AF:

0.792

Gnomad FIN

AF:

0.869

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.861

Gnomad OTH

AF:

0.787

GnomAD2 exomes

AF:

0.806

AC:

201112

AN:

249436

AF XY:

0.813

show subpopulations

Gnomad AFR exome

AF:

0.608

Gnomad AMR exome

AF:

0.745

Gnomad ASJ exome

AF:

0.806

Gnomad EAS exome

AF:

0.712

Gnomad FIN exome

AF:

0.865

Gnomad NFE exome

AF:

0.859

Gnomad OTH exome

AF:

0.811

GnomAD4 exome

AF:

0.842

AC:

1210948

AN:

1438988

Hom.:

512354

Cov.:

AF XY:

0.840

AC XY:

602764

AN XY:

717338

show subpopulations

African (AFR)

AF:

0.597

AC:

19629

AN:

32902

American (AMR)

AF:

0.748

AC:

33310

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.805

AC:

20897

AN:

25948

East Asian (EAS)

AF:

0.650

AC:

25714

AN:

39560

South Asian (SAS)

AF:

0.795

AC:

68153

AN:

85690

European-Finnish (FIN)

AF:

0.863

AC:

46038

AN:

53352

Middle Eastern (MID)

AF:

0.815

AC:

4414

AN:

5414

European-Non Finnish (NFE)

AF:

0.864

AC:

943809

AN:

1092014

Other (OTH)

AF:

0.822

AC:

48984

AN:

59604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

10122

20245

30367

40490

50612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20650

41300

61950

82600

103250

<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:

0.773

AC:

117539

AN:

152070

Hom.:

46340

Cov.:

AF XY:

0.773

AC XY:

57461

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.610

AC:

25298

AN:

41440

American (AMR)

AF:

0.766

AC:

11716

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.792

AC:

2747

AN:

3468

East Asian (EAS)

AF:

0.698

AC:

3602

AN:

5160

South Asian (SAS)

AF:

0.792

AC:

3813

AN:

4812

European-Finnish (FIN)

AF:

0.869

AC:

9211

AN:

10594

Middle Eastern (MID)

AF:

0.827

AC:

243

AN:

294

European-Non Finnish (NFE)

AF:

0.861

AC:

58501

AN:

67984

Other (OTH)

AF:

0.783

AC:

1653

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1299

2598

3896

5195

6494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

866

1732

2598

3464

4330

<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:

0.828

Hom.:

92050

Bravo

AF:

0.759

Asia WGS

AF:

0.710

AC:

2468

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Distal myopathy with anterior tibial onset

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Miyoshi muscular dystrophy 1

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.6

(source)

DANN

Benign

0.60

PhyloP100

-0.68

Mutation Taster

=100/0

polymorphism (auto)

(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