2-71503282-A-G

Position:

chr2-71503282-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000410020.8(DYSF):c.308A>G(p.Asn103Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,614,070 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N103N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

DYSF
ENST00000410020.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.982

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06640121).

BP6

Variant 2-71503282-A-G is Benign according to our data. Variant chr2-71503282-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538621.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.308A>G	p.Asn103Ser	missense_variant	4/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.305A>G	p.Asn102Ser	missense_variant	4/55	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.308A>G	p.Asn103Ser	missense_variant	4/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.305A>G	p.Asn102Ser	missense_variant	4/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000251

AC:

AN:

251438

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000492

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000309

AC:

451

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

227

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000388

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000118

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000185

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 29, 2016

- -

Qualitative or quantitative defects of dysferlin

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

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

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.020

MetaRNN

Benign

0.066

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

0.98

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

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.6

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

REVEL

Benign

0.035

Sift

Benign

0.045

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

Sift4G

Benign

0.19

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

Polyphen

0.0020

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

Vest4

0.28

MVP

0.70

MPC

0.13

ClinPred

0.060

GERP RS

3.8

Varity_R

0.24

gMVP

0.11

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