chr2-71555922-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001130987.2(DYSF):c.2110-43G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,490,578 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 33 hom., cov: 33)

Exomes 𝑓: 0.020 ( 315 hom. )

Consequence

DYSF
NM_001130987.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.24

Publications

0 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=-0.65).

BP6

Variant 2-71555922-G-T is Benign according to our data. Variant chr2-71555922-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2607/152326) while in subpopulation NFE AF = 0.0254 (1727/68008). AF 95% confidence interval is 0.0244. There are 33 homozygotes in GnomAd4. There are 1285 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.2110-43G>T		intron_variant	Intron 21 of 55	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.2056-43G>T		intron_variant	Intron 21 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.2110-43G>T		intron_variant	Intron 21 of 55	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.2056-43G>T		intron_variant	Intron 21 of 54	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2607

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00806

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0254

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0135

AC:

2093

AN:

154846

AF XY:

0.0131

show subpopulations

Gnomad AFR exome

AF:

0.00578

Gnomad AMR exome

AF:

0.00740

Gnomad ASJ exome

AF:

0.00787

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0250

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0136

GnomAD4 exome

AF:

0.0198

AC:

26474

AN:

1338252

Hom.:

315

Cov.:

AF XY:

0.0191

AC XY:

12686

AN XY:

663458

show subpopulations

African (AFR)

AF:

0.00704

AC:

214

AN:

30412

American (AMR)

AF:

0.00736

AC:

262

AN:

35618

Ashkenazi Jewish (ASJ)

AF:

0.00751

AC:

186

AN:

24774

East Asian (EAS)

AF:

0.00

AC:

AN:

35526

South Asian (SAS)

AF:

0.000154

AC:

AN:

77928

European-Finnish (FIN)

AF:

0.0284

AC:

1396

AN:

49226

Middle Eastern (MID)

AF:

0.00115

AC:

AN:

5232

European-Non Finnish (NFE)

AF:

0.0230

AC:

23522

AN:

1023578

Other (OTH)

AF:

0.0157

AC:

876

AN:

55958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1290

2580

3869

5159

6449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.0171

AC:

2607

AN:

152326

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1285

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00803

AC:

334

AN:

41572

American (AMR)

AF:

0.00999

AC:

153

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0322

AC:

342

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0254

AC:

1727

AN:

68008

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

142

285

427

570

712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0234

Hom.:

Bravo

AF:

0.0143

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 19, 2018

GeneDx

Significance:Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.096

(source)

DANN

Benign

0.57

PhyloP100

-1.2

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