2-71515762-T-C

Position:

• chr2-71515762-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.888+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,613,846 control chromosomes in the GnomAD database, including 14,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1378 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13275 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.467

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=-0.89).
• BP6: Variant 2-71515762-T-C is Benign according to our data. Variant chr2-71515762-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71515762-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.888+11T>C		intron_variant		ENST00000410020.8
DYSF	NM_003494.4	c.792+11T>C		intron_variant		ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.792+11T>C		intron_variant		1	NM_003494.4	A1
DYSF	ENST00000410020.8	c.888+11T>C		intron_variant		1	NM_001130987.2	A1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20123 AN: 151996 Hom.: 1374 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0297

Gnomad SAS AF: 0.0817

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.140

GnomAD3 exomes AF: 0.115 AC: 28795 AN: 251150 Hom.: 1778 AF XY: 0.115 AC XY: 15617 AN XY: 135748

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.0298

Gnomad SAS exome AF: 0.0875

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.131 AC: 192192 AN: 1461732 Hom.: 13275 Cov.: 33 AF XY: 0.130 AC XY: 94538 AN XY: 727160

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.0786

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.0248

Gnomad4 SAS exome AF: 0.0911

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.133 AC: 20156 AN: 152114 Hom.: 1378 Cov.: 33 AF XY: 0.132 AC XY: 9810 AN XY: 74366

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.0297

Gnomad4 SAS AF: 0.0814

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.138

Alfa AF: 0.125 Hom.: 838

Bravo AF: 0.130

Asia WGS AF: 0.0510 AC: 180 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.888+11T>C in intron 8 of DYSF: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 14.9% (656/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs13428076). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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 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. -

Limb-girdle muscular dystrophy, recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Distal myopathy with anterior tibial onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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	-0.89
CADD	Benign	4.8
DANN	Benign	0.56

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: rs13428076; hg19: chr2-71742892;