rs7573406

chr2-71644058-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001130987.2(DYSF):c.4621C>T(p.Leu1541=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00823 in 1,609,458 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0081 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (83 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 1.23

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-71644058-C-T is Benign according to our data. Variant chr2-71644058-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94325.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=6, Likely_benign=1}. Variant chr2-71644058-C-T is described in Lovd as [Benign]. Variant chr2-71644058-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00824 (12006/1457166) while in subpopulation MID AF= 0.0328 (188/5728). AF 95% confidence interval is 0.029. There are 83 homozygotes in gnomad4_exome. There are 6262 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.4621C>T	p.Leu1541=	synonymous_variant	42/56	ENST00000410020.8
DYSF	NM_003494.4	c.4504C>T	p.Leu1502=	synonymous_variant	41/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.4621C>T	p.Leu1541=	synonymous_variant	42/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.4504C>T	p.Leu1502=	synonymous_variant	41/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1237 AN: 152174 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00794

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00908

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00791 AC: 1919 AN: 242576 Hom.: 14 AF XY: 0.00878 AC XY: 1148 AN XY: 130704

Gnomad AFR exome AF: 0.00751

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.0171

Gnomad FIN exome AF: 0.00247

Gnomad NFE exome AF: 0.00812

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.00824 AC: 12006 AN: 1457166 Hom.: 83 Cov.: 32 AF XY: 0.00865 AC XY: 6262 AN XY: 724268

Gnomad4 AFR exome AF: 0.00775

Gnomad4 AMR exome AF: 0.00687

Gnomad4 ASJ exome AF: 0.00959

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0170

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.00788

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00815 AC: 1241 AN: 152292 Hom.: 7 Cov.: 33 AF XY: 0.00784 AC XY: 584 AN XY: 74482

Gnomad4 AFR AF: 0.00799

Gnomad4 AMR AF: 0.00883

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00908

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00872 Hom.: 3

Bravo AF: 0.00868

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 13, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 22, 2021	- -
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.Leu1541Leu in exon 42 of DYSF: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.8% (34/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs7573406). -
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	GeneDx	May 19, 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. -

Qualitative or quantitative defects of dysferlin Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Limb-Girdle Muscular Dystrophy, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Miyoshi myopathy Uncertain:1

Uncertain significance, 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 muscular dystrophy 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	4.2
Dann	Benign	0.50

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: rs7573406; hg19: chr2-71871188; COSMIC: COSV50435908; COSMIC: COSV50435908;