2-71526334-G-A

Position:

chr2-71526334-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001130987.2(DYSF):c.1264G>A(p.Asp422Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,583,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.84

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a domain C2 3 (size 136) in uniprot entity DYSF_HUMAN there are 42 pathogenic changes around while only 4 benign (91%) in NM_001130987.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

PP5

Variant 2-71526334-G-A is Pathogenic according to our data. Variant chr2-71526334-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 282410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71526334-G-A is described in Lovd as [Pathogenic]. Variant chr2-71526334-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-71526334-G-A 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.1264G>A	p.Asp422Asn	missense_variant	13/56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 linkuse as main transcript	c.1168G>A	p.Asp390Asn	missense_variant	12/55	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.1264G>A	p.Asp422Asn	missense_variant	13/56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.1168G>A	p.Asp390Asn	missense_variant	12/55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250594

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135504

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1432368

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

712200

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:

0.0000146

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150772

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73608

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely 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

Jun 02, 2023

Variant summary: DYSF c.1168G>A (p.Asp390Asn) results in a conservative amino acid change located in the 3rd C2 repeat domain (IPR000008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250594 control chromosomes (gnomAD). c.1168G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive, including two 2 affected individuals in the same family (e.g. Krahn_2009, Cerino_2020, Charnay_2021, Kergourlay_2015), and in multiple cases the absence of the dysferlin protein on western blot / immunohisto-chemistry was noted. These data indicate that the variant is very likely to be associated with disease. One publication reported that this variant has no effect on splicing in a mini-gene assay (Kergourlay_2014), however these results do not allow conclusions about the protein level effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 18853459, 32934002, 33927379, 26273692, 25312915). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 04, 2016

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Apr 07, 2017

- -

Miyoshi muscular dystrophy 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 15, 2024

- -

Qualitative or quantitative defects of dysferlin

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 390 of the DYSF protein (p.Asp390Asn). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with distal myopathy (PMID: 18853459, 25783436, 26273692). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 282410). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYSF protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

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

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.86

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

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.8

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

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.5

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

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0050

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

Polyphen

0.99

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

Vest4

0.83

MutPred

0.19

.;.;Gain of catalytic residue at D390 (P = 0.0203);.;Gain of catalytic residue at D390 (P = 0.0203);.;.;.;.;.;.;

MVP

0.87

MPC

0.64

ClinPred

0.99

GERP RS

5.5

Varity_R

0.92

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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