2-71539161-C-T

Position:

chr2-71539161-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

The NM_001130987.2(DYSF):c.1498C>T(p.Arg500Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,613,970 control chromosomes in the GnomAD database, including 1 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 0.00054 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.77

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2953723).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000539 (82/152150) while in subpopulation AMR AF= 0.00445 (68/15282). AF 95% confidence interval is 0.0036. There are 1 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 link	c.1498C>T	p.Arg500Cys	missense_variant	17/56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 link	c.1402C>T	p.Arg468Cys	missense_variant	16/55	ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 link	c.1498C>T	p.Arg500Cys	missense_variant	17/56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 link	c.1402C>T	p.Arg468Cys	missense_variant	16/55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00446

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251474

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000539

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000318

Hom.:

Bravo

AF:

0.00115

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2016	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 25, 2023	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Qualitative or quantitative defects of dysferlin

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

.;.;.;.;D;.;.;.;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.055

MetaRNN

Benign

0.30

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

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.8

.;.;M;.;M;.;.;.;.;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.7

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

REVEL

Uncertain

0.56

Sift

Uncertain

0.020

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

Sift4G

Uncertain

0.057

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

Polyphen

0.97

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

Vest4

0.77

MVP

0.87

MPC

0.30

ClinPred

0.53

GERP RS

5.0

Varity_R

0.67

gMVP

0.72

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

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