rs143762717

Positions:

• chr2-71682530-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The NM_001130987.2(DYSF):​c.6174G>A​(p.Arg2058=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (1 hom.)
• Consequence: DYSF NM_001130987.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: 1.84

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-71682530-G-A is Benign according to our data. Variant chr2-71682530-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197967.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.6174G>A	p.Arg2058=	splice_region_variant, synonymous_variant	55/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.6057G>A	p.Arg2019=	splice_region_variant, synonymous_variant	54/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.6174G>A	p.Arg2058=	splice_region_variant, synonymous_variant	55/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.6057G>A	p.Arg2019=	splice_region_variant, synonymous_variant	54/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000485 AC: 122 AN: 251478 Hom.: 1 AF XY: 0.000515 AC XY: 70 AN XY: 135918

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000934 AC: 1365 AN: 1461886 Hom.: 1 Cov.: 31 AF XY: 0.000903 AC XY: 657 AN XY: 727246

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74402

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000868

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000992 Hom.: 0

Bravo AF: 0.000544

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 29, 2021	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing;provider interpretation	Kids Neuroscience Centre, Sydney Children's Hospitals Network	-	No evidence that the c.6057G>A variant affects the splicing of DYSF mRNA. This variant is synonymous p.(Arg2019=) and is not predicted to impact the DYSF protein. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 13, 2020	- -

Qualitative or quantitative defects of dysferlin Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

Limb-girdle muscular dystrophy, recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Miyoshi myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DYSF-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.090		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: rs143762717; hg19: chr2-71909660;