chr19-46756181-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024301.5(FKRP):c.731G>A(p.Arg244His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,439,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:1

Conservation

PhyloP100: 0.0810

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20556077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.731G>A	p.Arg244His	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FKRP	ENST00000318584.10 link	c.731G>A	p.Arg244His	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4	Q9H9S5
FKRP	ENST00000391909.7 link	c.731G>A	p.Arg244His	missense_variant	Exon 4 of 4	2		ENSP00000375776.2	Q9H9S5
FKRP	ENST00000597339.5 link	n.247-5652G>A		intron_variant	Intron 3 of 3	5
FKRP	ENST00000600646.5 link	n.247+7516G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.000258

AC:

AN:

151140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00106

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000295

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000266

Gnomad OTH

AF:

0.000962

GnomAD3 exomes

AF:

0.000348

AC:

AN:

57478

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

34034

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000870

Gnomad ASJ exome

AF:

0.000212

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000799

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000403

Gnomad OTH exome

AF:

0.000558

GnomAD4 exome

AF:

0.000111

AC:

143

AN:

1288044

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

633324

show subpopulations

Gnomad4 AFR exome

AF:

0.0000401

Gnomad4 AMR exome

AF:

0.000848

Gnomad4 ASJ exome

AF:

0.0000944

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000145

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.000283

GnomAD4 genome

AF:

0.000258

AC:

AN:

151248

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

73914

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000295

Gnomad4 NFE

AF:

0.000266

Gnomad4 OTH

AF:

0.000951

Bravo

AF:

0.000325

ExAC

AF:

0.0000299

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:4

Sep 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Immunohistochemical analysis noted a depletion of alpha-dystroglycan glycosylation and mildly reduced alpha-dystroglycan on muscle biopsy from the patient (Boito et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 16344347, 26990548, 17952692, 30564623) -

Nov 30, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:2

Feb 19, 2025

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.731G>A (p.Arg244His) results in a non-conservative amino acid change located in the fukutin-related protein stem domain (IPR055105) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 57478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FKRP causing Autosomal recessive limb-girdle muscular dystrophy type 2I (0.00035 vs 0.011), allowing no conclusion about variant significance. c.731G>A has been reported in the literature in at least one homozygous individual affected with Autosomal recessive limb-girdle muscular dystrophy type 2I (e.g., Boito_2005, Boito_2007), without strong evidence for causality. These data indicate that the variant may be associated with disease. Muscle biopsy analysis of this homozygous patient showed conflicting results indicating that glycosylated alpha-dystroglycan levels were possibly (but not clearly) decreased vs. controls (Boito_2005, Boito_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17952692, 16344347). ClinVar contains an entry for this variant (Variation ID: 283038). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jun 30, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Uncertain:2

Dec 16, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R244H variant (also known as c.731G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 731. The arginine at codon 244 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in a homozygous individual with limb girdle muscular dystrophy, including myalgia, more affected lower limbs than upper, and no muscle hypertrophy; muscle biopsy results showed some reduction in glycosylated alpha-dystroglycan expression compared to controls (Boito CA et al. Arch. Neurol., 2005 Dec;62:1894-9; Boito CA et al. Virchows Arch., 2007 Dec;451:1047-55). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Walker-Warburg congenital muscular dystrophy

Benign:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.010

CADD

Benign

8.5

DANN

Benign

0.96

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.52

.;T

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.21

T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

0.34

N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.60

Sift

Benign

0.21

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0010

B;B

Vest4

0.054

MutPred

0.70

Loss of solvent accessibility (P = 0.0128);Loss of solvent accessibility (P = 0.0128);

MVP

0.77

MPC

0.78

ClinPred

0.015

GERP RS

0.98

Varity_R

0.060

gMVP

0.68

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