rs1555738483

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5

The NM_024301.5(FKRP):c.502T>C(p.Cys168Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,383,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C168Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 4.30

Publications

1 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 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_024301.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-46755953-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1334893.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.835

PP5

Variant 19-46755952-T-C is Pathogenic according to our data. Variant chr19-46755952-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 557519.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.502T>C	p.Cys168Arg	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10 link	c.502T>C	p.Cys168Arg	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1383754

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31234

American (AMR)

AF:

0.00

AC:

AN:

35676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25014

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35746

South Asian (SAS)

AF:

0.00

AC:

AN:

79210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079020

Other (OTH)

AF:

0.00

AC:

AN:

57816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

Pathogenic:1

Mar 09, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Apr 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FKRP c.502T>C (p.Cys168Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.502T>C has been reported in the literature in one individual affected with congenital muscular dystrophy type 1C, Autosomal Recessive (Fu_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27439679, 32864802). ClinVar contains an entry for this variant (Variation ID: 557519). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Uncertain:1

Mar 28, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;D;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.060

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.57

.;T;T

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

1.8

L;L;.

PhyloP100

4.3

PrimateAI

Pathogenic

0.98

PROVEAN

Pathogenic

-7.8

D;D;.

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.93

MutPred

0.63

Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);.;

MVP

0.88

MPC

2.2

ClinPred

1.0

GERP RS

3.5

Varity_R

0.97

gMVP

0.98

Mutation Taster

=0/100

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