rs12470028

Positions:

• chr2-71481990-G-A
• chr2-71481990-G-T

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.239+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0807 in 1,601,178 control chromosomes in the GnomAD database, including 6,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (733 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5924 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0680

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=-0.9).
• BP6: Variant 2-71481990-G-A is Benign according to our data. Variant chr2-71481990-G-A is described in ClinVar as [Benign]. Clinvar id is 94288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71481990-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.239+20G>A		intron_variant		ENST00000410020.8
DYSF	NM_003494.4	c.236+20G>A		intron_variant		ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.236+20G>A		intron_variant		1	NM_003494.4	A1
DYSF	ENST00000410020.8	c.239+20G>A		intron_variant		1	NM_001130987.2	A1

Frequencies

GnomAD3 genomes AF: 0.0899 AC: 13678 AN: 152102 Hom.: 734 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.0862

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0733

Gnomad OTH AF: 0.0883

GnomAD3 exomes AF: 0.0974 AC: 24269 AN: 249230 Hom.: 1989 AF XY: 0.0911 AC XY: 12266 AN XY: 134608

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.0465

Gnomad EAS exome AF: 0.0150

Gnomad SAS exome AF: 0.0919

Gnomad FIN exome AF: 0.0324

Gnomad NFE exome AF: 0.0753

Gnomad OTH exome AF: 0.0850

GnomAD4 exome AF: 0.0797 AC: 115446 AN: 1448958 Hom.: 5924 Cov.: 27 AF XY: 0.0788 AC XY: 56824 AN XY: 721570

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.265

Gnomad4 ASJ exome AF: 0.0462

Gnomad4 EAS exome AF: 0.0158

Gnomad4 SAS exome AF: 0.0929

Gnomad4 FIN exome AF: 0.0361

Gnomad4 NFE exome AF: 0.0751

Gnomad4 OTH exome AF: 0.0805

GnomAD4 genome AF: 0.0900 AC: 13695 AN: 152220 Hom.: 733 Cov.: 32 AF XY: 0.0886 AC XY: 6594 AN XY: 74434

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.0157

Gnomad4 SAS AF: 0.0867

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.0733

Gnomad4 OTH AF: 0.0874

Alfa AF: 0.0778 Hom.: 304

Bravo AF: 0.106

Asia WGS AF: 0.0490 AC: 171 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.51

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: rs12470028; hg19: chr2-71709120; COSMIC: COSV50305430;