rs398123779

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_001130987.2(DYSF):c.3245_3250dup(p.Ala1082_Glu1083dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.05 in 1,613,284 control chromosomes in the GnomAD database, including 2,265 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 157 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2108 hom. )

Consequence

DYSF
NM_001130987.2 inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 4.19

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 -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001130987.2.

BP6

Variant 2-71574204-C-CAGGCGG is Benign according to our data. Variant chr2-71574204-C-CAGGCGG is described in ClinVar as [Likely_benign]. Clinvar id is 94301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.3245_3250dup	p.Ala1082_Glu1083dup	inframe_insertion	30/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.3191_3196dup	p.Ala1064_Glu1065dup	inframe_insertion	30/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8 linkuse as main transcript	c.3191_3196dup	p.Ala1064_Glu1065dup	inframe_insertion	30/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1
DYSF	ENST00000410020.8 linkuse as main transcript	c.3245_3250dup	p.Ala1082_Glu1083dup	inframe_insertion	30/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13

Frequencies

GnomAD3 genomes

AF:

0.0405

AC:

6164

AN:

152198

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0113

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.0561

Gnomad ASJ

AF:

0.0449

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0225

Gnomad FIN

AF:

0.0337

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0587

Gnomad OTH

AF:

0.0532

GnomAD3 exomes

AF:

0.0395

AC:

9796

AN:

248130

Hom.:

275

AF XY:

0.0412

AC XY:

5551

AN XY:

134722

show subpopulations

Gnomad AFR exome

AF:

0.00835

Gnomad AMR exome

AF:

0.0359

Gnomad ASJ exome

AF:

0.0488

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0245

Gnomad FIN exome

AF:

0.0299

Gnomad NFE exome

AF:

0.0560

Gnomad OTH exome

AF:

0.0490

GnomAD4 exome

AF:

0.0510

AC:

74557

AN:

1460968

Hom.:

2108

Cov.:

AF XY:

0.0505

AC XY:

36713

AN XY:

726802

show subpopulations

Gnomad4 AFR exome

AF:

0.00875

Gnomad4 AMR exome

AF:

0.0379

Gnomad4 ASJ exome

AF:

0.0462

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0240

Gnomad4 FIN exome

AF:

0.0299

Gnomad4 NFE exome

AF:

0.0577

Gnomad4 OTH exome

AF:

0.0514

GnomAD4 genome

AF:

0.0405

AC:

6163

AN:

152316

Hom.:

157

Cov.:

AF XY:

0.0399

AC XY:

2971

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0113

Gnomad4 AMR

AF:

0.0561

Gnomad4 ASJ

AF:

0.0449

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0226

Gnomad4 FIN

AF:

0.0337

Gnomad4 NFE

AF:

0.0587

Gnomad4 OTH

AF:

0.0527

Alfa

AF:

0.0486

Hom.:

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0632

EpiControl

AF:

0.0611

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 19, 2014	p.Ala1082_Glu1083dup in exon 30 of DYSF: This variant is a duplication of 2 amin o acids at position 1082 and is not predicted to alter the protein reading-frame . This variant is not expected to have clinical significance because it has been identified in 5.6% (453/8150) of European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 24, 2015	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	This variant is associated with the following publications: (PMID: 19528035, 15469449, 14678801, 31862442) -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Limb-girdle muscular dystrophy, recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Distal myopathy with anterior tibial onset

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Miyoshi muscular dystrophy 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Miyoshi myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Qualitative or quantitative defects of dysferlin

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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