2-71611314-A-G

Position:

chr2-71611314-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_001130987.2(DYSF):c.4027A>G(p.Ile1343Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,613,996 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0039 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 3 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 9.32

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 -7 ACMG points.

PM1

In a domain C2 5 (size 128) in uniprot entity DYSF_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) in NM_001130987.2

BP4

Computational evidence support a benign effect (MetaRNN=0.008916825).

BP6

Variant 2-71611314-A-G is Benign according to our data. Variant chr2-71611314-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 336969.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=3}. Variant chr2-71611314-A-G is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.4027A>G	p.Ile1343Val	missense_variant	37/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.3973A>G	p.Ile1325Val	missense_variant	37/55	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.4027A>G	p.Ile1343Val	missense_variant	37/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.3973A>G	p.Ile1325Val	missense_variant	37/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.00392

AC:

597

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.00144

GnomAD3 exomes

AF:

0.000905

AC:

227

AN:

250768

Hom.:

AF XY:

0.000583

AC XY:

AN XY:

135538

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.000376

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:

0.0000265

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000436

AC:

637

AN:

1461696

Hom.:

Cov.:

AF XY:

0.000399

AC XY:

290

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0150

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.00392

AC:

597

AN:

152300

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0140

Gnomad4 AMR

AF:

0.000522

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:

0.00142

Alfa

AF:

0.000714

Hom.:

Bravo

AF:

0.00441

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00115

AC:

140

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Qualitative or quantitative defects of dysferlin

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Limb-girdle muscular dystrophy, recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Miyoshi myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 05, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2021

This variant is associated with the following publications: (PMID: 18853459) -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

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

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

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

MetaRNN

Benign

0.0089

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

MetaSVM

Uncertain

-0.0061

MutationAssessor

Uncertain

2.2

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.83

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

REVEL

Uncertain

0.39

Sift

Uncertain

0.027

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

Sift4G

Uncertain

0.037

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

Polyphen

0.26

B;B;P;B;B;P;P;B;B;B;B

Vest4

0.67

MVP

0.72

MPC

0.33

ClinPred

0.052

GERP RS

4.7

Varity_R

0.13

gMVP

0.49

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