rs35721373

chr2-71553118-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130987.2(DYSF):c.1914C>T(p.Tyr638=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,614,130 control chromosomes in the GnomAD database, including 913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (95 hom., cov: 33)
  • Exomes 𝑓: 0.030 (818 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -3.52

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-71553118-C-T is Benign according to our data. Variant chr2-71553118-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71553118-C-T is described in Lovd as [Benign]. Variant chr2-71553118-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.1914C>T	p.Tyr638=	synonymous_variant	20/56	ENST00000410020.8
DYSF	NM_003494.4	c.1860C>T	p.Tyr620=	synonymous_variant	20/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.1914C>T	p.Tyr638=	synonymous_variant	20/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.1860C>T	p.Tyr620=	synonymous_variant	20/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 5030 AN: 152192 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.0585

Gnomad FIN AF: 0.00913

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0302

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0286 AC: 7180 AN: 251438 Hom.: 154 AF XY: 0.0300 AC XY: 4078 AN XY: 135906

Gnomad AFR exome AF: 0.0528

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.00837

Gnomad SAS exome AF: 0.0584

Gnomad FIN exome AF: 0.00711

Gnomad NFE exome AF: 0.0298

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0300 AC: 43914 AN: 1461820 Hom.: 818 Cov.: 34 AF XY: 0.0310 AC XY: 22569 AN XY: 727210

Gnomad4 AFR exome AF: 0.0550

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.0217

Gnomad4 EAS exome AF: 0.00844

Gnomad4 SAS exome AF: 0.0574

Gnomad4 FIN exome AF: 0.00809

Gnomad4 NFE exome AF: 0.0295

Gnomad4 OTH exome AF: 0.0322

GnomAD4 genome AF: 0.0331 AC: 5039 AN: 152310 Hom.: 95 Cov.: 33 AF XY: 0.0320 AC XY: 2381 AN XY: 74488

Gnomad4 AFR AF: 0.0507

Gnomad4 AMR AF: 0.0179

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.0590

Gnomad4 FIN AF: 0.00913

Gnomad4 NFE AF: 0.0302

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0318 Hom.: 35

Bravo AF: 0.0336

Asia WGS AF: 0.0480 AC: 167 AN: 3478

EpiCase AF: 0.0333

EpiControl AF: 0.0304

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Tyr638Tyr in exon 20 of DYSF: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 4.7% (209/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35721373). -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 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. -

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	- -

Qualitative or quantitative defects of dysferlin Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Distal myopathy with anterior tibial onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Limb-Girdle Muscular Dystrophy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Miyoshi muscular dystrophy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

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	-0.62
Cadd	Benign	2.6
Dann	Benign	0.63

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

Other links and lift over

dbSNP: rs35721373; hg19: chr2-71780248; COSMIC: COSV50516165;