NM_024301.5:c.206C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP2PP3

The NM_024301.5(FKRP):c.206C>T(p.Ser69Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S69P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.04

Publications

0 publications found

Variant links:

Genes affected

FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

FKRP Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy type 2I
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics
muscular dystrophy-dystroglycanopathy type B5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
myopathy caused by variation in FKRP
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
congenital muscular dystrophy with cerebellar involvement
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy with intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy without intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscle-eye-brain disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscular dystrophy-dystroglycanopathy, type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FKRP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-46755655-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 999725.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.8498 (below the threshold of 3.09). Trascript score misZ: -2.4986 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, muscular dystrophy-dystroglycanopathy, type A, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.206C>T	p.Ser69Phe	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10 link	c.206C>T	p.Ser69Phe	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1444976

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719004

African (AFR)

AF:

0.00

AC:

AN:

33270

American (AMR)

AF:

0.00

AC:

AN:

44322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25942

East Asian (EAS)

AF:

0.00

AC:

AN:

39326

South Asian (SAS)

AF:

0.00

AC:

AN:

85110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109614

Other (OTH)

AF:

0.00

AC:

AN:

60052

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

May 24, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

Walker-Warburg congenital muscular dystrophy

Uncertain:1

Jan 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine with phenylalanine at codon 69 of the FKRP protein (p.Ser69Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FKRP-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

.;D;.;D;.;.;.;.;.;.;.;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

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

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.79

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.8

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

PhyloP100

4.0

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.71, 0.72

MutPred

0.29

Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);

MVP

0.99

MPC

1.6

ClinPred

0.99

GERP RS

4.8

Varity_R

0.83

gMVP

0.96

Mutation Taster

=5/95

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over