rs35884879

Positions:

chr2-71568027-A-C

Variant summary

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

The ENST00000410020.8(DYSF):c.2642A>C(p.Asp881Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000974 in 1,614,090 control chromosomes in the GnomAD database, including 12 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. D881E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0053 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 6 hom. )

Consequence

DYSF
ENST00000410020.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.48

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=0.009132832).

BP6

Variant 2-71568027-A-C is Benign according to our data. Variant chr2-71568027-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 167019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71568027-A-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00534 (813/152218) while in subpopulation AFR AF= 0.0188 (780/41514). AF 95% confidence interval is 0.0177. There are 6 homozygotes in gnomad4. There are 396 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.2642A>C	p.Asp881Ala	missense_variant	25/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.2588A>C	p.Asp863Ala	missense_variant	25/55	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.2642A>C	p.Asp881Ala	missense_variant	25/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.2588A>C	p.Asp863Ala	missense_variant	25/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.00535

AC:

814

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.0000441

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00143

AC:

359

AN:

251492

Hom.:

AF XY:

0.00110

AC XY:

150

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0206

Gnomad AMR exome

AF:

0.000607

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:

0.00000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000519

AC:

759

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000459

AC XY:

334

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0195

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.00534

AC:

813

AN:

152218

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

396

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0188

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.000950

Hom.:

Bravo

AF:

0.00620

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00185

AC:

225

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2013	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 11, 2018	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 10, 2019

- -

Qualitative or quantitative defects of dysferlin

Benign:1

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

Uncertain

0.42

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

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

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

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

MetaRNN

Benign

0.0091

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

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.1

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.9

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

REVEL

Uncertain

0.64

Sift

Benign

0.13

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

Sift4G

Benign

0.52

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

Polyphen

0.20

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

Vest4

0.80

MVP

0.86

MPC

0.44

ClinPred

0.039

GERP RS

5.0

Varity_R

0.48

gMVP

0.77

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