2-71568330-G-A

Position:

chr2-71568330-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001130987.2(DYSF):c.2856G>A(p.Pro952=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,614,078 control chromosomes in the GnomAD database, including 1,366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 88 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1278 hom. )

Consequence

DYSF
NM_001130987.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -4.77

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 2-71568330-G-A is Benign according to our data. Variant chr2-71568330-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71568330-G-A is described in Lovd as [Benign]. Variant chr2-71568330-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-4.77 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3825/152286) while in subpopulation NFE AF= 0.0385 (2616/68018). AF 95% confidence interval is 0.0372. There are 88 homozygotes in gnomad4. There are 1797 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 88 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.2856G>A	p.Pro952=	synonymous_variant	26/56	ENST00000410020.8
DYSF	NM_003494.4 linkuse as main transcript	c.2802G>A	p.Pro934=	synonymous_variant	26/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.2856G>A	p.Pro952=	synonymous_variant	26/56	1	NM_001130987.2	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.2802G>A	p.Pro934=	synonymous_variant	26/55	1	NM_003494.4	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3826

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00663

Gnomad AMI

AF:

0.0604

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0622

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0350

Gnomad FIN

AF:

0.0152

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0385

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.0278

AC:

6968

AN:

250236

Hom.:

138

AF XY:

0.0294

AC XY:

3973

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.00573

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.0667

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0365

Gnomad FIN exome

AF:

0.0180

Gnomad NFE exome

AF:

0.0367

Gnomad OTH exome

AF:

0.0308

GnomAD4 exome

AF:

0.0386

AC:

56414

AN:

1461792

Hom.:

1278

Cov.:

AF XY:

0.0385

AC XY:

28007

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00541

Gnomad4 AMR exome

AF:

0.0112

Gnomad4 ASJ exome

AF:

0.0684

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0379

Gnomad4 FIN exome

AF:

0.0187

Gnomad4 NFE exome

AF:

0.0425

Gnomad4 OTH exome

AF:

0.0387

GnomAD4 genome

AF:

0.0251

AC:

3825

AN:

152286

Hom.:

Cov.:

AF XY:

0.0241

AC XY:

1797

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00661

Gnomad4 AMR

AF:

0.0182

Gnomad4 ASJ

AF:

0.0622

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0348

Gnomad4 FIN

AF:

0.0152

Gnomad4 NFE

AF:

0.0385

Gnomad4 OTH

AF:

0.0223

Alfa

AF:

0.0348

Hom.:

Bravo

AF:

0.0244

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Pro952Pro in exon 26 of DYSF: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 4.3% (370/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34836829). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Qualitative or quantitative defects of dysferlin

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.59

DANN

Benign

0.71

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