2-71612671-C-T

Position:

chr2-71612671-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4BP6

The NM_001130987.2(DYSF):c.4252C>T(p.Pro1418Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P1418P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.44

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 Uncertain_significance. Variant got 2 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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38607678).

BP6

Variant 2-71612671-C-T is Benign according to our data. Variant chr2-71612671-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1525577.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.4252C>T	p.Pro1418Ser	missense_variant	39/56	ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 linkuse as main transcript	c.4198C>T	p.Pro1400Ser	missense_variant	39/55	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.4252C>T	p.Pro1418Ser	missense_variant	39/56	1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.4198C>T	p.Pro1400Ser	missense_variant	39/55	1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251316

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727224

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:

0.0000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 04, 2020

- -

Qualitative or quantitative defects of dysferlin

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

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

Eigen

Benign

0.033

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.057

MetaRNN

Benign

0.39

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

MetaSVM

Uncertain

0.050

MutationAssessor

Uncertain

2.5

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

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.3

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

REVEL

Uncertain

0.41

Sift

Benign

0.055

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

Sift4G

Benign

0.063

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

Polyphen

0.065

B;B;B;B;B;B;B;B;B;B;B

Vest4

0.34

MVP

0.81

MPC

0.22

ClinPred

0.80

GERP RS

4.6

Varity_R

0.34

gMVP

0.80

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