NM_024301.5:c.541C>A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_024301.5(FKRP):c.541C>A(p.Arg181Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,545,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.725

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 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 strand (size 5) in uniprot entity FKRP_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_024301.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17834076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.541C>A	p.Arg181Ser	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.541C>A	p.Arg181Ser	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000737

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000700

AC:

AN:

142926

Hom.:

AF XY:

0.000101

AC XY:

AN XY:

79102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000394

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000878

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000139

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1393360

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

689216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000272

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:

0.0000580

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000737

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000274

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 14, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency 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 supports that this missense variant does not alter protein structure/function; Reported as heterozygous in an individual with autism and neuromuscular weakness; however, a second FKRP variant was not reported (Athey 2020) -

Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

Uncertain:1

Nov 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Uncertain:1

Jan 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R181S variant (also known as c.541C>A), located in coding exon 1 of the FKRP gene, results from a C to A substitution at nucleotide position 541. The arginine at codon 181 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Walker-Warburg congenital muscular dystrophy

Uncertain:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 181 of the FKRP protein (p.Arg181Ser). This variant is present in population databases (rs777245868, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FKRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 528815). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Benign

0.15

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.67

.;T

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.18

T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

-0.69

N;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.70

N;N

REVEL

Uncertain

0.44

Sift

Benign

0.42

T;T

Sift4G

Benign

0.74

T;T

Polyphen

0.0

B;B

Vest4

0.10

MutPred

0.28

Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);

MVP

0.84

MPC

0.71

ClinPred

0.018

GERP RS

2.3

Varity_R

0.39

gMVP

0.67

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