rs12713756

Positions:

• chr2-71520769-G-A

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.1034-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 1,609,198 control chromosomes in the GnomAD database, including 216,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18082 hom., cov: 31)
  • Exomes 𝑓: 0.51 (198112 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.11

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-71520769-G-A is Benign according to our data. Variant chr2-71520769-G-A is described in ClinVar as [Benign]. Clinvar id is 94368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71520769-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.1034-20G>A		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.938-20G>A		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.938-20G>A		intron_variant		1	NM_003494.4	ENSP00000258104	A1
DYSF	ENST00000410020.8	c.1034-20G>A		intron_variant		1	NM_001130987.2	ENSP00000386881	A1

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72615 AN: 151778 Hom.: 18069 Cov.: 31

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.495

GnomAD3 exomes AF: 0.479 AC: 120394 AN: 251342 Hom.: 30984 AF XY: 0.478 AC XY: 64899 AN XY: 135852

Gnomad AFR exome AF: 0.409

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.106

Gnomad SAS exome AF: 0.386

Gnomad FIN exome AF: 0.552

Gnomad NFE exome AF: 0.536

Gnomad OTH exome AF: 0.507

GnomAD4 exome AF: 0.515 AC: 749790 AN: 1457302 Hom.: 198112 Cov.: 30 AF XY: 0.512 AC XY: 371145 AN XY: 725330

Gnomad4 AFR exome AF: 0.410

Gnomad4 AMR exome AF: 0.526

Gnomad4 ASJ exome AF: 0.582

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.385

Gnomad4 FIN exome AF: 0.555

Gnomad4 NFE exome AF: 0.539

Gnomad4 OTH exome AF: 0.497

GnomAD4 genome AF: 0.478 AC: 72676 AN: 151896 Hom.: 18082 Cov.: 31 AF XY: 0.472 AC XY: 35039 AN XY: 74208

Gnomad4 AFR AF: 0.411

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.587

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.547

Gnomad4 NFE AF: 0.534

Gnomad4 OTH AF: 0.493

Alfa AF: 0.519 Hom.: 7081

Bravo AF: 0.474

Asia WGS AF: 0.254 AC: 888 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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, 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+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Distal myopathy with anterior tibial onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

- -

Qualitative or quantitative defects of dysferlin Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0020
DANN	Benign	0.38

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: rs12713756; hg19: chr2-71747899; COSMIC: COSV50432691;