rs115013641

chr2-71669705-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_001130987.2(DYSF):c.5743G>A(p.Asp1915Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,614,120 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (27 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 2.78

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 -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001130987.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.010743886).
• BP6: Variant 2-71669705-G-A is Benign according to our data. Variant chr2-71669705-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71669705-G-A is described in Lovd as [Benign]. Variant chr2-71669705-G-A is described in Lovd as [Likely_benign]. Variant chr2-71669705-G-A is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.5743G>A	p.Asp1915Asn	missense_variant	51/56	ENST00000410020.8
DYSF	NM_003494.4	c.5626G>A	p.Asp1876Asn	missense_variant	50/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.5743G>A	p.Asp1915Asn	missense_variant	51/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.5626G>A	p.Asp1876Asn	missense_variant	50/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152118 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00396 AC: 996 AN: 251492 Hom.: 11 AF XY: 0.00437 AC XY: 594 AN XY: 135920

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00866

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00355 AC: 5188 AN: 1461884 Hom.: 27 Cov.: 32 AF XY: 0.00378 AC XY: 2752 AN XY: 727242

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00846

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00324

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152236 Hom.: 6 Cov.: 33 AF XY: 0.00277 AC XY: 206 AN XY: 74432

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00397 Hom.: 3

Bravo AF: 0.00306

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00610

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DYSF: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2018	This variant is associated with the following publications: (PMID: 25525159, 21522182, 17897828, 22046204, 24838345) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Athena Diagnostics	Nov 09, 2018	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2022	Variant summary: DYSF c.5626G>A (p.Asp1876Asn) results in a conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 251492 control chromosomes, predominantly at a frequency of 0.0087 within the South Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=4) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Qualitative or quantitative defects of dysferlin Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 31, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 15, 2019

- -

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C5553104:Miyoshi myopathy Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Uncertain significance and reported on 01-23-2012 by Lab or GTR ID 1012. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Benign	0.095
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	0.66	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.044	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.051	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.33	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.42
MVP		0.85
MPC		0.29
ClinPred		0.020	T
GERP RS		3.9
Varity_R		0.35
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs115013641; hg19: chr2-71896835; COSMIC: COSV99247624;