rs35392229

chr2-71513828-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001130987.2(DYSF):c.666T>C(p.Pro222=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,614,128 control chromosomes in the GnomAD database, including 1,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (125 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1240 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.11

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=-0.83).
• BP6: Variant 2-71513828-T-C is Benign according to our data. Variant chr2-71513828-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71513828-T-C is described in Lovd as [Likely_benign]. Variant chr2-71513828-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0315 (4793/152254) while in subpopulation NFE AF= 0.0404 (2748/68000). AF 95% confidence interval is 0.0392. There are 125 homozygotes in gnomad4. There are 2552 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 125 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.666T>C	p.Pro222=	synonymous_variant	7/56	ENST00000410020.8
DYSF	NM_003494.4	c.570T>C	p.Pro190=	synonymous_variant	6/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.666T>C	p.Pro222=	synonymous_variant	7/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.570T>C	p.Pro190=	synonymous_variant	6/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4798 AN: 152136 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.00750

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0404

Gnomad OTH AF: 0.0368

GnomAD3 exomes AF: 0.0332 AC: 8358 AN: 251416 Hom.: 211 AF XY: 0.0339 AC XY: 4604 AN XY: 135896

Gnomad AFR exome AF: 0.00640

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0122

Gnomad FIN exome AF: 0.0910

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0337

GnomAD4 exome AF: 0.0382 AC: 55854 AN: 1461874 Hom.: 1240 Cov.: 32 AF XY: 0.0375 AC XY: 27251 AN XY: 727238

Gnomad4 AFR exome AF: 0.00597

Gnomad4 AMR exome AF: 0.0228

Gnomad4 ASJ exome AF: 0.00918

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.0882

Gnomad4 NFE exome AF: 0.0419

Gnomad4 OTH exome AF: 0.0316

GnomAD4 genome AF: 0.0315 AC: 4793 AN: 152254 Hom.: 125 Cov.: 32 AF XY: 0.0343 AC XY: 2552 AN XY: 74456

Gnomad4 AFR AF: 0.00748

Gnomad4 AMR AF: 0.0334

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00912

Gnomad4 FIN AF: 0.0943

Gnomad4 NFE AF: 0.0404

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0352 Hom.: 41

Bravo AF: 0.0270

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0387

EpiControl AF: 0.0405

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 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	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

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

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Limb-Girdle Muscular Dystrophy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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	-0.83
Cadd	Benign	3.9
Dann	Benign	0.52

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: rs35392229; hg19: chr2-71740958;