rs34603128

chr2-71511857-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.396C>T(p.Pro132=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,551,400 control chromosomes in the GnomAD database, including 12,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1677 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10355 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.263

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=-0.47).
• BP6: Variant 2-71511857-C-T is Benign according to our data. Variant chr2-71511857-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71511857-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.263 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.396C>T	p.Pro132=	synonymous_variant	5/56	ENST00000410020.8
DYSF	NM_003494.4	c.393C>T	p.Pro131=	synonymous_variant	5/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.396C>T	p.Pro132=	synonymous_variant	5/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.393C>T	p.Pro131=	synonymous_variant	5/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21070 AN: 152118 Hom.: 1675 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.104 AC: 16380 AN: 156760 Hom.: 1074 AF XY: 0.102 AC XY: 8385 AN XY: 82490

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.0899

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.0106

Gnomad SAS exome AF: 0.0569

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.117 AC: 164029 AN: 1399164 Hom.: 10355 Cov.: 32 AF XY: 0.115 AC XY: 79441 AN XY: 690112

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.0932

Gnomad4 ASJ exome AF: 0.0674

Gnomad4 EAS exome AF: 0.00646

Gnomad4 SAS exome AF: 0.0589

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.139 AC: 21090 AN: 152236 Hom.: 1677 Cov.: 33 AF XY: 0.137 AC XY: 10181 AN XY: 74444

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.0602

Gnomad4 EAS AF: 0.0125

Gnomad4 SAS AF: 0.0505

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.141

Alfa AF: 0.128 Hom.: 677

Bravo AF: 0.142

Asia WGS AF: 0.0420 AC: 148 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Pro132Pro in exon 5 of DYSF: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 16.8% (663/3952) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34603128). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 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	-	- -

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	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 13, 2017

- -

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	-0.47
Cadd	Benign	8.0
Dann	Benign	0.84

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

Other links and lift over

dbSNP: rs34603128; hg19: chr2-71738987;