dbSNP rs2303596: DYSF:p.Asp627Asp (chr2-71553085-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001130987.2(DYSF):c.1881T>C(p.Asp627Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,613,950 control chromosomes in the GnomAD database, including 395,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 38068 hom., cov: 32)

Exomes 𝑓: 0.69 ( 357627 hom. )

Consequence

DYSF
NM_001130987.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -2.58

Publications

29 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 2-71553085-T-C is Benign according to our data. Variant chr2-71553085-T-C is described in ClinVar as Benign. ClinVar VariationId is 94281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.58 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DYSF	NM_001130987.2	MANE Select	c.1881T>C	p.Asp627Asp	synonymous	Exon 20 of 56	NP_001124459.1	O75923-13
DYSF	NM_003494.4	MANE Plus Clinical	c.1827T>C	p.Asp609Asp	synonymous	Exon 20 of 55	NP_003485.1	O75923-1
DYSF	NM_001130981.2		c.1878T>C	p.Asp626Asp	synonymous	Exon 20 of 56	NP_001124453.1	O75923-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DYSF	ENST00000410020.8	TSL:1 MANE Select	c.1881T>C	p.Asp627Asp	synonymous	Exon 20 of 56	ENSP00000386881.3	O75923-13
DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1827T>C	p.Asp609Asp	synonymous	Exon 20 of 55	ENSP00000258104.3	O75923-1
DYSF	ENST00000409582.7	TSL:1	c.1878T>C	p.Asp626Asp	synonymous	Exon 20 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

106068

AN:

151996

Hom.:

38021

Cov.:

show subpopulations

Gnomad AFR

AF:

0.779

Gnomad AMI

AF:

0.776

Gnomad AMR

AF:

0.635

Gnomad ASJ

AF:

0.754

Gnomad EAS

AF:

0.198

Gnomad SAS

AF:

0.502

Gnomad FIN

AF:

0.687

Gnomad MID

AF:

0.704

Gnomad NFE

AF:

0.712

Gnomad OTH

AF:

0.695

GnomAD2 exomes

AF:

0.641

AC:

161254

AN:

251388

AF XY:

0.640

show subpopulations

Gnomad AFR exome

AF:

0.784

Gnomad AMR exome

AF:

0.617

Gnomad ASJ exome

AF:

0.743

Gnomad EAS exome

AF:

0.173

Gnomad FIN exome

AF:

0.689

Gnomad NFE exome

AF:

0.712

Gnomad OTH exome

AF:

0.666

GnomAD4 exome

AF:

0.692

AC:

1012266

AN:

1461834

Hom.:

357627

Cov.:

AF XY:

0.689

AC XY:

500766

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.784

AC:

26242

AN:

33478

American (AMR)

AF:

0.624

AC:

27895

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.743

AC:

19413

AN:

26136

East Asian (EAS)

AF:

0.214

AC:

8513

AN:

39700

South Asian (SAS)

AF:

0.542

AC:

46757

AN:

86258

European-Finnish (FIN)

AF:

0.695

AC:

37087

AN:

53386

Middle Eastern (MID)

AF:

0.692

AC:

3994

AN:

5768

European-Non Finnish (NFE)

AF:

0.721

AC:

801432

AN:

1111992

Other (OTH)

AF:

0.678

AC:

40933

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

20044

40089

60133

80178

100222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19806

39612

59418

79224

99030

<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:

0.698

AC:

106173

AN:

152116

Hom.:

38068

Cov.:

AF XY:

0.688

AC XY:

51139

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.779

AC:

32345

AN:

41498

American (AMR)

AF:

0.635

AC:

9718

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.754

AC:

2618

AN:

3470

East Asian (EAS)

AF:

0.198

AC:

1020

AN:

5162

South Asian (SAS)

AF:

0.503

AC:

2426

AN:

4826

European-Finnish (FIN)

AF:

0.687

AC:

7274

AN:

10584

Middle Eastern (MID)

AF:

0.707

AC:

208

AN:

294

European-Non Finnish (NFE)

AF:

0.712

AC:

48402

AN:

67972

Other (OTH)

AF:

0.691

AC:

1456

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1575

3150

4724

6299

7874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

808

1616

2424

3232

4040

<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:

0.710

Hom.:

81190

Bravo

AF:

0.699

Asia WGS

AF:

0.389

AC:

1357

AN:

3478

EpiCase

AF:

0.715

EpiControl

AF:

0.716

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Autosomal recessive limb-girdle muscular dystrophy type 2B (2)

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)

not provided (2)

Distal myopathy with anterior tibial onset (1)

Limb-girdle muscular dystrophy, recessive (1)

Miyoshi muscular dystrophy 1 (1)

Miyoshi myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.79

(source)

DANN

Benign

0.48

PhyloP100

-2.6

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over