rs61740288

chr2-71535283-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001130987.2(DYSF):c.1465G>A(p.Glu489Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,613,910 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (30 hom., cov: 31)
  • Exomes 𝑓: 0.020 (372 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 8.91

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 -11 ACMG points.

• PM1: In a domain C2 3 (size 136) in uniprot entity DYSF_HUMAN there are 52 pathogenic changes around while only 18 benign (74%) in NM_001130987.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.009779274).
• BP6: Variant 2-71535283-G-A is Benign according to our data. Variant chr2-71535283-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94270.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6, Likely_benign=1}. Variant chr2-71535283-G-A is described in Lovd as [Benign]. Variant chr2-71535283-G-A is described in Lovd as [Likely_benign]. Variant chr2-71535283-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2608/152134) while in subpopulation NFE AF= 0.0244 (1657/67976). AF 95% confidence interval is 0.0234. There are 30 homozygotes in gnomad4. There are 1261 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.1465G>A	p.Glu489Lys	missense_variant	16/56	ENST00000410020.8
DYSF	NM_003494.4	c.1369G>A	p.Glu457Lys	missense_variant	15/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.1465G>A	p.Glu489Lys	missense_variant	16/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.1369G>A	p.Glu457Lys	missense_variant	15/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2611 AN: 152016 Hom.: 30 Cov.: 31

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0314

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0171 AC: 4291 AN: 251472 Hom.: 64 AF XY: 0.0174 AC XY: 2362 AN XY: 135908

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.00847

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00728

Gnomad FIN exome AF: 0.0255

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0202 AC: 29528 AN: 1461776 Hom.: 372 Cov.: 33 AF XY: 0.0200 AC XY: 14532 AN XY: 727182

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.00988

Gnomad4 ASJ exome AF: 0.0294

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.00751

Gnomad4 FIN exome AF: 0.0237

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0189

GnomAD4 genome AF: 0.0171 AC: 2608 AN: 152134 Hom.: 30 Cov.: 31 AF XY: 0.0170 AC XY: 1261 AN XY: 74354

Gnomad4 AFR AF: 0.00448

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0314

Gnomad4 NFE AF: 0.0244

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0233 Hom.: 80

Bravo AF: 0.0158

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0245 AC: 211

ExAC AF: 0.0170 AC: 2065

EpiCase AF: 0.0267

EpiControl AF: 0.0273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DYSF: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 25312915, 22995991, 31862442, 20981092, 17698709, 27884173, 21522182, 25214167) -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0098	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.43
MPC		0.58
ClinPred		0.030	T
GERP RS		4.8
Varity_R		0.74
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61740288; hg19: chr2-71762413; COSMIC: COSV50471313;