Genetic Variant DYSF:c.1985-31C>T (chr2-71553776-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001130987.2(DYSF):c.1985-31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 675,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000074 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.964

Publications

1 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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	Effect	Exon Rank	Protein	UniProt
DYSF	NM_001130987.2	MANE Select	c.1985-31C>T	intron	N/A	NP_001124459.1	O75923-13
DYSF	NM_003494.4	MANE Plus Clinical	c.1931-31C>T	intron	N/A	NP_003485.1	O75923-1
DYSF	NM_001130981.2		c.1982-31C>T	intron	N/A	NP_001124453.1	O75923-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DYSF	ENST00000410020.8	TSL:1 MANE Select	c.1985-31C>T	intron	N/A	ENSP00000386881.3	O75923-13
DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1931-31C>T	intron	N/A	ENSP00000258104.3	O75923-1
DYSF	ENST00000409582.7	TSL:1	c.1982-31C>T	intron	N/A	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes

AF:

0.0000372

AC:

AN:

134300

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000227

AC:

AN:

220410

AF XY:

0.00000845

show subpopulations

Gnomad AFR exome

AF:

0.000365

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000740

AC:

AN:

540886

Hom.:

Cov.:

AF XY:

0.00000695

AC XY:

AN XY:

287800

show subpopulations

African (AFR)

AF:

0.000327

AC:

AN:

12226

American (AMR)

AF:

0.00

AC:

AN:

34880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14334

East Asian (EAS)

AF:

0.00

AC:

AN:

12978

South Asian (SAS)

AF:

0.00

AC:

AN:

65932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31780

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3128

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

342988

Other (OTH)

AF:

0.00

AC:

AN:

22640

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000372

AC:

AN:

134394

Hom.:

Cov.:

AF XY:

0.0000311

AC XY:

AN XY:

64266

show subpopulations

African (AFR)

AF:

0.000137

AC:

AN:

36622

American (AMR)

AF:

0.00

AC:

AN:

12838

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3292

East Asian (EAS)

AF:

0.00

AC:

AN:

3628

South Asian (SAS)

AF:

0.00

AC:

AN:

3706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63626

Other (OTH)

AF:

0.00

AC:

AN:

1932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.6

(source)

DANN

Benign

0.70

PhyloP100

0.96

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over