rs84182

Positions:

• chr2-71644106-A-G
• chr2-71644106-A-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.4626+43A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,501,960 control chromosomes in the GnomAD database, including 570,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57360 hom., cov: 31)
  • Exomes 𝑓: 0.87 (512949 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.13

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 2-71644106-A-G is Benign according to our data. Variant chr2-71644106-A-G is described in ClinVar as [Benign]. Clinvar id is 259080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71644106-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4626+43A>G		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4509+43A>G		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4626+43A>G		intron_variant		1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4509+43A>G		intron_variant		1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131840 AN: 152038 Hom.: 57324 Cov.: 31

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.837

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.843

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.857

GnomAD3 exomes AF: 0.845 AC: 170153 AN: 201330 Hom.: 72285 AF XY: 0.850 AC XY: 91206 AN XY: 107296

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.717

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.815

Gnomad SAS exome AF: 0.846

Gnomad FIN exome AF: 0.859

Gnomad NFE exome AF: 0.881

Gnomad OTH exome AF: 0.850

GnomAD4 exome AF: 0.871 AC: 1175651 AN: 1349804 Hom.: 512949 Cov.: 20 AF XY: 0.871 AC XY: 585829 AN XY: 672776

Gnomad4 AFR exome AF: 0.898

Gnomad4 AMR exome AF: 0.720

Gnomad4 ASJ exome AF: 0.858

Gnomad4 EAS exome AF: 0.788

Gnomad4 SAS exome AF: 0.848

Gnomad4 FIN exome AF: 0.857

Gnomad4 NFE exome AF: 0.882

Gnomad4 OTH exome AF: 0.865

GnomAD4 genome AF: 0.867 AC: 131925 AN: 152156 Hom.: 57360 Cov.: 31 AF XY: 0.862 AC XY: 64166 AN XY: 74400

Gnomad4 AFR AF: 0.898

Gnomad4 AMR AF: 0.788

Gnomad4 ASJ AF: 0.843

Gnomad4 EAS AF: 0.804

Gnomad4 SAS AF: 0.834

Gnomad4 FIN AF: 0.860

Gnomad4 NFE AF: 0.876

Gnomad4 OTH AF: 0.848

Alfa AF: 0.867 Hom.: 10572

Bravo AF: 0.862

Asia WGS AF: 0.797 AC: 2771 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

not specified Benign:1

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.59

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: rs84182; hg19: chr2-71871236;