rs11903960

chr2-71516246-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130987.2(DYSF):c.951+4T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 1,613,410 control chromosomes in the GnomAD database, including 6,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (748 hom., cov: 33)
  • Exomes 𝑓: 0.089 (6196 hom.)
• Consequence: DYSF NM_001130987.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00002590
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-71516246-T-C is Benign according to our data. Variant chr2-71516246-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71516246-T-C is described in Lovd as [Benign]. Variant chr2-71516246-T-C is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.951+4T>C		splice_donor_region_variant, intron_variant		ENST00000410020.8
DYSF	NM_003494.4	c.855+4T>C		splice_donor_region_variant, intron_variant		ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.855+4T>C		splice_donor_region_variant, intron_variant		1	NM_003494.4	A1
DYSF	ENST00000410020.8	c.951+4T>C		splice_donor_region_variant, intron_variant		1	NM_001130987.2	A1

Frequencies

GnomAD3 genomes AF: 0.0965 AC: 14678 AN: 152158 Hom.: 746 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0820

Gnomad ASJ AF: 0.0960

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0886

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.0792 AC: 19913 AN: 251300 Hom.: 875 AF XY: 0.0782 AC XY: 10628 AN XY: 135832

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.0594

Gnomad ASJ exome AF: 0.0948

Gnomad EAS exome AF: 0.0299

Gnomad SAS exome AF: 0.0473

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0884

Gnomad OTH exome AF: 0.0794

GnomAD4 exome AF: 0.0889 AC: 129862 AN: 1461134 Hom.: 6196 Cov.: 32 AF XY: 0.0872 AC XY: 63350 AN XY: 726900

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.0610

Gnomad4 ASJ exome AF: 0.0979

Gnomad4 EAS exome AF: 0.0247

Gnomad4 SAS exome AF: 0.0499

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.0932

Gnomad4 OTH exome AF: 0.0912

GnomAD4 genome AF: 0.0965 AC: 14697 AN: 152276 Hom.: 748 Cov.: 33 AF XY: 0.0968 AC XY: 7209 AN XY: 74470

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0822

Gnomad4 ASJ AF: 0.0960

Gnomad4 EAS AF: 0.0292

Gnomad4 SAS AF: 0.0452

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0886

Gnomad4 OTH AF: 0.104

Alfa AF: 0.0913 Hom.: 917

Bravo AF: 0.0972

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.0891

EpiControl AF: 0.0866

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.951+4T>C in intron 9 of DYSF: This variant is not expected to have clinical si gnificance because it has been identified in 12.5% (551/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs11903960). -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 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. -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Qualitative or quantitative defects of dysferlin Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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 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	-0.80
Cadd	Benign	0.0010
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0080
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: rs11903960; hg19: chr2-71743376;