chr2-71660641-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2

The NM_001130987.2(DYSF):c.4993G>A(p.Val1665Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000247 in 1,613,842 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).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 3 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:8

Conservation

PhyloP100: 4.27

Variant links:

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]

DYSF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1

In a domain C2 6 (size 118) in uniprot entity DYSF_HUMAN there are 26 pathogenic changes around while only 4 benign (87%) in NM_001130987.2

BP4

Computational evidence support a benign effect (MetaRNN=0.01881209).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000381 (58/152342) while in subpopulation EAS AF= 0.00983 (51/5186). AF 95% confidence interval is 0.00768. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.4993G>A	p.Val1665Ile	missense_variant	Exon 45 of 56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.4876G>A	p.Val1626Ile	missense_variant	Exon 44 of 55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.4993G>A	p.Val1665Ile	missense_variant	Exon 45 of 56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.4876G>A	p.Val1626Ile	missense_variant	Exon 44 of 55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00981

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000736

AC:

185

AN:

251312

Hom.:

AF XY:

0.000670

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00963

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000233

AC:

341

AN:

1461500

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

176

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00703

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000381

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00983

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000573

Hom.:

Bravo

AF:

0.000461

ExAC

AF:

0.000700

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:2

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYSF: BS1 -

Jun 15, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Jul 01, 2019

Department of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: reference population

- -

not specified

Benign:3

Jan 18, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DYSF c.4876G>A (p.Val1626Ile) results in a conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 251312 control chromosomes, predominantly at a frequency of 0.0096 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East 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 East Asian origin. It has also been reported at a frequency of 0.0044 in control individuals of Japanese ancestry in the Japanese Whole Genome Reference Panel (ToMMo 38KJPN), including 3 homozygotes. c.4876G>A has been reported in the literature in individuals of East Asian ancestry affected with or suspected of Limb-Girdle Muscular Dystrophy/Dysferlinopathy, without strong evidence for pathogenicity, including one case where it was found in cis with a pathogenic variant, providing supporting evidence for a benign role (e.g. Yu_2017, Liu_2018, Zhong_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority classified the variant as benign (n=1)/likely benign (n=4), two classified the variant as VUS, and one as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -

Nov 24, 2020

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:1Benign:1

Jan 08, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Qualitative or quantitative defects of dysferlin

Uncertain:1Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

DYSF-related disorder

Benign:1

Mar 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

0.083

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

.;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.032

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.019

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.4

.;.;.;.;L;.;.;.;.;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.42

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.41

T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.74

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.022

B;B;B;B;B;B;B;B;B;B;B

Vest4

0.33

MVP

0.54

MPC

0.12

ClinPred

0.022

GERP RS

5.8

Varity_R

0.12

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over