rs145272777

chr2-71667391-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001130987.2(DYSF):c.5333C>A(p.Pro1778Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:4
• Conservation: PhyloP100: -0.0560

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009371072).
• BP6: Variant 2-71667391-C-A is Benign according to our data. Variant chr2-71667391-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285686.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.5333C>A	p.Pro1778Gln	missense_variant	48/56	ENST00000410020.8
DYSF	NM_003494.4	c.5216C>A	p.Pro1739Gln	missense_variant	47/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.5333C>A	p.Pro1778Gln	missense_variant	48/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.5216C>A	p.Pro1739Gln	missense_variant	47/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000562 AC: 141 AN: 250878 Hom.: 0 AF XY: 0.000604 AC XY: 82 AN XY: 135742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000350 AC: 511 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.000378 AC XY: 275 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74472

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000653 Hom.: 1

Bravo AF: 0.000382

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000519 AC: 63

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2020	This variant is associated with the following publications: (PMID: 30564623, 27647186) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 10, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -

Miyoshi muscular dystrophy 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2018	The DYSF gene is the only gene in which variants are known to cause dysferlinopathy. The DYSF c.5216C>A (p.Pro1739Gln) missense variant has been reported in one study in which it is found in two siblings from a family with a history of dysferlinopathy. The variant was found in a compound heterozygous state with a deletion in one sibling and in a heterozygous state in the other (Jin et al. 2016). Both siblings were found to be negative for dysferlin expression using immunohistochemical analysis of muscle tissue (Jin et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.005924 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Pro1739Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Distal myopathy with anterior tibial onset Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

DYSF-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2019

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
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.86
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.85	D;T;T;D;D;D;D;T;T;T;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.0094	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.066	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.71	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.40
MVP		0.70
MPC		0.14
ClinPred		0.013	T
GERP RS		3.3
Varity_R		0.047
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145272777; hg19: chr2-71894521;