2-71570679-C-T

Position:

chr2-71570679-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001130987.2(DYSF):c.3166C>T(p.Arg1056Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 1.22

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-71570679-C-T is Pathogenic according to our data. Variant chr2-71570679-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 217225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71570679-C-T is described in Lovd as [Pathogenic]. Variant chr2-71570679-C-T is described in Lovd as [Pathogenic]. Variant chr2-71570679-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.3166C>T	p.Arg1056Ter	stop_gained	29/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.3112C>T	p.Arg1038Ter	stop_gained	29/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.3166C>T	p.Arg1056Ter	stop_gained	29/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.3112C>T	p.Arg1038Ter	stop_gained	29/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250626

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000669

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 09, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 05, 2017	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Arg1056Ter (sometimes called p.Arg1038Ter) variant in DYSF was identified by our study in two siblings with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.002442% (6/245656) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs369607332). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported in ClinVar (Variation ID: 217225). The presence of this variant in combination with a frameshift variant and in an individual with limb-girdle muscular dystrophy (LGMD) increases the likelihood that the p.Arg1056Ter variant is pathogenic. (PMID: 23243261). This nonsense variant leads to a premature termination codon at position 1056, which is predicted to lead to a truncated or absent protein. Loss of function of the DYSF gene is an established disease mechanism in autosomal recessive LGMD, and this is a loss of function variant. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and a report of this variant with another loss of function variant in the literature. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015). -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	Observed with a pathogenic variant in published literature but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Nguyen et al., 2005; Takahashi et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as a patient harboring the Q1278X variant was found to have absent/drastically reduced dysferlin expression on western blot analysis (Nguyen et al., 2005); This variant is associated with the following publications: (PMID: 23254335, 21173544, 25591676, 18853459, 25525159, 16010686, 19528035, 23243261, 32528171) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 28, 2023	- -

Qualitative or quantitative defects of dysferlin

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 29, 2017	The DYSF c.3112C>T (p.Arg1038Ter) variant has been reported in six studies and identified in seven individuals, including three in a homozygous state and four in a compound heterozygous state (Nguyen et al. 2005; Choi et al. 2010; Zhao et al. 2013; Takahashi et al. 2013; Xi et al. 2014; Liu et al. 2015). Five of the affected individuals had a clinical diagnosis of Miyoshi myopathy and two had limb-girdle muscular dystrophy type 2B. The p.Arg1038Ter variant was absent from 100 controls but is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the clinical evidence and the potential impact of stop-gained variants, the p.Arg1038Ter variant is classified as pathogenic for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	This sequence change creates a premature translational stop signal (p.Arg1038*) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs369607332, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Miyoshi Myopathy (PMID: 16010686, 20497525, 23243261, 23254335). ClinVar contains an entry for this variant (Variation ID: 217225). For these reasons, this variant has been classified as Pathogenic. -

Miyoshi muscular dystrophy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 05, 2024

- -

Abnormality of the musculature

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.77

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A

Vest4

0.95

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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