2-71598667-C-G

Position:

chr2-71598667-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001130987.2(DYSF):c.3678C>G(p.Ile1226Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,614,106 control chromosomes in the GnomAD database, including 1 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 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00082 ( 1 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.01

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018383056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.3678C>G	p.Ile1226Met	missense_variant	33/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.3624C>G	p.Ile1208Met	missense_variant	33/55	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.3678C>G	p.Ile1226Met	missense_variant	33/56	1	NM_001130987.2	ENSP00000386881	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.3624C>G	p.Ile1208Met	missense_variant	33/55	1	NM_003494.4	ENSP00000258104	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000696

AC:

175

AN:

251294

Hom.:

AF XY:

0.000640

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000792

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000815

AC:

1192

AN:

1461778

Hom.:

Cov.:

AF XY:

0.000770

AC XY:

560

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00448

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.000878

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152328

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000911

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000965

Hom.:

Bravo

AF:

0.000793

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 27, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2018	This variant is associated with the following publications: (PMID: 26764160, 16010686, 25900324, 32528171) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DYSF: BP4 -

Qualitative or quantitative defects of dysferlin

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.080

CADD

Benign

3.9

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

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

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.018

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

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

0.98

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

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.2

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

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.045

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

Polyphen

0.98

D;P;P;D;D;D;D;P;D;D;D

Vest4

0.59

MVP

0.68

MPC

0.63

ClinPred

0.33

GERP RS

-4.4

Varity_R

0.45

gMVP

0.47

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