rs34211915

Positions:

chr2-71570632-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000410020.8(DYSF):c.3119G>A(p.Arg1040Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0213 in 1,614,056 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1040W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.025 ( 57 hom., cov: 33)

Exomes 𝑓: 0.021 ( 389 hom. )

Consequence

DYSF
ENST00000410020.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 4.75

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072483122).

BP6

Variant 2-71570632-G-A is Benign according to our data. Variant chr2-71570632-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71570632-G-A is described in Lovd as [Likely_benign]. Variant chr2-71570632-G-A is described in Lovd as [Benign]. Variant chr2-71570632-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-71570632-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0246 (3746/152310) while in subpopulation AFR AF= 0.0348 (1447/41552). AF 95% confidence interval is 0.0333. There are 57 homozygotes in gnomad4. There are 1826 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.3119G>A	p.Arg1040Gln	missense_variant	29/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.3065G>A	p.Arg1022Gln	missense_variant	29/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.3119G>A	p.Arg1040Gln	missense_variant	29/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.3065G>A	p.Arg1022Gln	missense_variant	29/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3745

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0349

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0385

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0243

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0184

AC:

4611

AN:

250548

Hom.:

AF XY:

0.0177

AC XY:

2404

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.0333

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.00786

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0330

Gnomad NFE exome

AF:

0.0249

Gnomad OTH exome

AF:

0.0192

GnomAD4 exome

AF:

0.0209

AC:

30594

AN:

1461746

Hom.:

389

Cov.:

AF XY:

0.0200

AC XY:

14576

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.0351

Gnomad4 AMR exome

AF:

0.0104

Gnomad4 ASJ exome

AF:

0.00723

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.0352

Gnomad4 NFE exome

AF:

0.0232

Gnomad4 OTH exome

AF:

0.0174

GnomAD4 genome

AF:

0.0246

AC:

3746

AN:

152310

Hom.:

Cov.:

AF XY:

0.0245

AC XY:

1826

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0348

Gnomad4 AMR

AF:

0.0119

Gnomad4 ASJ

AF:

0.00691

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0385

Gnomad4 NFE

AF:

0.0243

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0225

Hom.:

Bravo

AF:

0.0226

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.0332

AC:

146

ESP6500EA

AF:

0.0187

AC:

161

ExAC

AF:

0.0199

AC:

2414

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0224

EpiControl

AF:

0.0199

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DYSF: PM5, BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Qualitative or quantitative defects of dysferlin

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

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

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

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

MetaRNN

Benign

0.0072

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

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.7

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.0

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

REVEL

Uncertain

0.39

Sift

Benign

0.59

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

Sift4G

Benign

0.58

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

Polyphen

0.17

B;P;D;P;D;P;D;D;D;P;B

Vest4

0.61

MPC

0.18

ClinPred

0.022

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.53

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

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