rs76402294

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001130987.2(DYSF):c.1577-1635C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,610,416 control chromosomes in the GnomAD database, including 467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 88 hom., cov: 31)

Exomes 𝑓: 0.021 ( 379 hom. )

Consequence

DYSF
NM_001130987.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.775

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.22).

BP6

Variant 2-71549406-C-G is Benign according to our data. Variant chr2-71549406-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 94275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71549406-C-G is described in Lovd as [Likely_benign]. Variant chr2-71549406-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0288 (4382/152110) while in subpopulation AFR AF= 0.0477 (1980/41472). AF 95% confidence interval is 0.046. There are 88 homozygotes in gnomad4. There are 2164 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 88 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.1577-1635C>G		intron_variant		ENST00000410020.8
DYSF	NM_003494.4 linkuse as main transcript	c.1522+15C>G		intron_variant		ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8 linkuse as main transcript	c.1522+15C>G		intron_variant		1	NM_003494.4	A1	O75923-1
DYSF	ENST00000410020.8 linkuse as main transcript	c.1577-1635C>G		intron_variant		1	NM_001130987.2	A1	O75923-13

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4371

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0477

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0271

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00906

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0414

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0204

Gnomad OTH

AF:

0.0273

GnomAD3 exomes

AF:

0.0212

AC:

5197

AN:

244708

Hom.:

AF XY:

0.0202

AC XY:

2666

AN XY:

132248

show subpopulations

Gnomad AFR exome

AF:

0.0459

Gnomad AMR exome

AF:

0.0263

Gnomad ASJ exome

AF:

0.00619

Gnomad EAS exome

AF:

0.00899

Gnomad SAS exome

AF:

0.00427

Gnomad FIN exome

AF:

0.0391

Gnomad NFE exome

AF:

0.0208

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0212

AC:

30942

AN:

1458306

Hom.:

379

Cov.:

AF XY:

0.0204

AC XY:

14822

AN XY:

725100

show subpopulations

Gnomad4 AFR exome

AF:

0.0453

Gnomad4 AMR exome

AF:

0.0252

Gnomad4 ASJ exome

AF:

0.00650

Gnomad4 EAS exome

AF:

0.00537

Gnomad4 SAS exome

AF:

0.00386

Gnomad4 FIN exome

AF:

0.0374

Gnomad4 NFE exome

AF:

0.0219

Gnomad4 OTH exome

AF:

0.0198

GnomAD4 genome

AF:

0.0288

AC:

4382

AN:

152110

Hom.:

Cov.:

AF XY:

0.0291

AC XY:

2164

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0477

Gnomad4 AMR

AF:

0.0274

Gnomad4 ASJ

AF:

0.00750

Gnomad4 EAS

AF:

0.00908

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.0414

Gnomad4 NFE

AF:

0.0204

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.00774

Hom.:

Bravo

AF:

0.0296

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Qualitative or quantitative defects of dysferlin

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Limb-girdle muscular dystrophy, recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Miyoshi myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

4.0

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over