chr2-71589591-A-G

Position:

chr2-71589591-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The ENST00000410020.8(DYSF):c.3403-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

DYSF
ENST00000410020.8 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.61

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:

DYSF (HGNC:):

DYSF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014622642 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.7, offset of -42, new splice context is: agtctccctgccacccccAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-71589591-A-G is Pathogenic according to our data. Variant chr2-71589591-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 196694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71589591-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.3403-2A>G		splice_acceptor_variant, intron_variant		ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 linkuse as main transcript	c.3349-2A>G		splice_acceptor_variant, intron_variant		ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.3403-2A>G		splice_acceptor_variant, intron_variant		1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.3349-2A>G		splice_acceptor_variant, intron_variant		1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251474

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000236

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 15, 2024

Variant summary: DYSF c.3349-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of DYSF function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies.The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes. c.3349-2A>G has been reported in the literature in at-least one individual affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Klinge_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19528035). ClinVar contains an entry for this variant (Variation ID: 196694). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 14, 2015

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Jun 28, 2017

- -

Miyoshi muscular dystrophy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 18, 2024

- -

Qualitative or quantitative defects of dysferlin

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

This sequence change affects an acceptor splice site in intron 30 of the DYSF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs370874727, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with clinical features of limb-girdle muscular dystrophy (PMID: 19528035; Invitae). ClinVar contains an entry for this variant (Variation ID: 196694). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

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

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.31

Position offset: -40

DS_AL_spliceai

0.99

Position offset: 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