rs148541407

Positions:

• chr2-71665253-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001130987.2(DYSF):​c.5266C>T​(p.Arg1756Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000835 in 1,614,180 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1756Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00067 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (2 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 1.17

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.084513456).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.5266C>T	p.Arg1756Trp	missense_variant	47/56	ENST00000410020.8
DYSF	NM_003494.4	c.5149C>T	p.Arg1717Trp	missense_variant	46/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.5266C>T	p.Arg1756Trp	missense_variant	47/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.5149C>T	p.Arg1717Trp	missense_variant	46/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000517 AC: 130 AN: 251468 Hom.: 0 AF XY: 0.000545 AC XY: 74 AN XY: 135900

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000985

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000852 AC: 1246 AN: 1461878 Hom.: 2 Cov.: 32 AF XY: 0.000825 AC XY: 600 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.000671 AC XY: 50 AN XY: 74480

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.000650

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000981

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DYSF: BP4 -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2022	Variant summary: DYSF c.5149C>T (p.Arg1717Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 251468 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00052 vs 0.0031), allowing no conclusion about variant significance. c.5149C>T has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Cacciottolo_2011, Nallamilli_2018). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 11, 2018	The DYSF c.5149C>T (p.Arg1717Trp) variant is a missense variant which has been reported in one individual with dysferlin deficiency in a compound heterozygous state with a second missense variant (Cacciottolo et al. 2011). The p.Arg1717Trp variant was absent from 1000 controls and is reported at a frequency of 0.00116 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Arg1717Trp 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.085	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.043	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.0	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.45
MVP		0.82
MPC		0.15
ClinPred		0.027	T
GERP RS		1.1
Varity_R		0.037
gMVP		0.58

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: rs148541407; hg19: chr2-71892383; COSMIC: COSV99250622;