2-71664231-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.5004-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 1,612,854 control chromosomes in the GnomAD database, including 582,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 48994 hom., cov: 31)

Exomes 𝑓: 0.85 ( 533871 hom. )

Consequence

DYSF
NM_001130987.2 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.734

Publications

6 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=-0.92).

BP6

Variant 2-71664231-C-T is Benign according to our data. Variant chr2-71664231-C-T is described in ClinVar as Benign. ClinVar VariationId is 259081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.5004-37C>T		intron_variant	Intron 45 of 55	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.4887-37C>T		intron_variant	Intron 44 of 54	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.5004-37C>T		intron_variant	Intron 45 of 55	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.4887-37C>T		intron_variant	Intron 44 of 54	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.798

AC:

121260

AN:

151970

Hom.:

49008

Cov.:

show subpopulations

Gnomad AFR

AF:

0.691

Gnomad AMI

AF:

0.837

Gnomad AMR

AF:

0.755

Gnomad ASJ

AF:

0.853

Gnomad EAS

AF:

0.686

Gnomad SAS

AF:

0.819

Gnomad FIN

AF:

0.856

Gnomad MID

AF:

0.896

Gnomad NFE

AF:

0.866

Gnomad OTH

AF:

0.804

GnomAD2 exomes

AF:

0.816

AC:

205013

AN:

251146

AF XY:

0.826

show subpopulations

Gnomad AFR exome

AF:

0.689

Gnomad AMR exome

AF:

0.699

Gnomad ASJ exome

AF:

0.868

Gnomad EAS exome

AF:

0.703

Gnomad FIN exome

AF:

0.855

Gnomad NFE exome

AF:

0.871

Gnomad OTH exome

AF:

0.828

GnomAD4 exome

AF:

0.853

AC:

1246058

AN:

1460766

Hom.:

533871

Cov.:

AF XY:

0.854

AC XY:

620576

AN XY:

726728

show subpopulations

African (AFR)

AF:

0.685

AC:

22927

AN:

33458

American (AMR)

AF:

0.702

AC:

31337

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.864

AC:

22554

AN:

26102

East Asian (EAS)

AF:

0.654

AC:

25911

AN:

39638

South Asian (SAS)

AF:

0.838

AC:

72096

AN:

86082

European-Finnish (FIN)

AF:

0.853

AC:

45469

AN:

53284

Middle Eastern (MID)

AF:

0.889

AC:

5121

AN:

5762

European-Non Finnish (NFE)

AF:

0.873

AC:

970141

AN:

1111452

Other (OTH)

AF:

0.837

AC:

50502

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

11409

22819

34228

45638

57047

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21236

42472

63708

84944

106180

<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:

0.797

AC:

121280

AN:

152088

Hom.:

48994

Cov.:

AF XY:

0.795

AC XY:

59127

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.691

AC:

28636

AN:

41464

American (AMR)

AF:

0.754

AC:

11533

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.853

AC:

2960

AN:

3472

East Asian (EAS)

AF:

0.685

AC:

3527

AN:

5148

South Asian (SAS)

AF:

0.818

AC:

3947

AN:

4826

European-Finnish (FIN)

AF:

0.856

AC:

9068

AN:

10590

Middle Eastern (MID)

AF:

0.888

AC:

261

AN:

294

European-Non Finnish (NFE)

AF:

0.866

AC:

58904

AN:

67984

Other (OTH)

AF:

0.796

AC:

1682

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1204

2408

3613

4817

6021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.838

Hom.:

71820

Bravo

AF:

0.784

Asia WGS

AF:

0.730

AC:

2540

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

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.92

CADD

Benign

0.030

(source)

DANN

Benign

0.44

PhyloP100

-0.73

Mutation Taster

=20/80

disease causing

(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