rs77138370

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_024301.5(FKRP):c.822C>G(p.Ile274Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,508,888 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. I274T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 5 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 1.13

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 was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_024301.5

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 muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy, type A, congenital muscular dystrophy without intellectual disability, muscular dystrophy-dystroglycanopathy type B5, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP.

BP4

Computational evidence support a benign effect (MetaRNN=0.006845355).

BP6

Variant 19-46756272-C-G is Benign according to our data. Variant chr19-46756272-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129058.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6, Benign=3}. Variant chr19-46756272-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00308 (467/151746) while in subpopulation AFR AF = 0.0103 (426/41508). AF 95% confidence interval is 0.00946. There are 3 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.822C>G	p.Ile274Met	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.822C>G	p.Ile274Met	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4	Q9H9S5
FKRP	ENST00000391909.7 link	c.822C>G	p.Ile274Met	missense_variant	Exon 4 of 4	2		ENSP00000375776.2	Q9H9S5
FKRP	ENST00000597339.5 link	n.247-5561C>G		intron_variant	Intron 3 of 3	5
FKRP	ENST00000600646.5 link	n.247+7607C>G		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00307

AC:

466

AN:

151638

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.000868

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.000687

AC:

AN:

114982

AF XY:

0.000493

show subpopulations

Gnomad AFR exome

AF:

0.00962

Gnomad AMR exome

AF:

0.000555

Gnomad ASJ exome

AF:

0.000943

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000466

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000315

AC:

427

AN:

1357142

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

167

AN XY:

667508

show subpopulations

Gnomad4 AFR exome

AF:

0.0109

AC:

333

AN:

30640

Gnomad4 AMR exome

AF:

0.000586

AC:

AN:

32408

Gnomad4 ASJ exome

AF:

0.000904

AC:

AN:

23226

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

35070

Gnomad4 SAS exome

AF:

0.0000265

AC:

AN:

75484

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

34806

Gnomad4 NFE exome

AF:

0.00000752

AC:

AN:

1064444

Gnomad4 Remaining exome

AF:

0.000709

AC:

AN:

56386

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00308

AC:

467

AN:

151746

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

195

AN XY:

74142

show subpopulations

Gnomad4 AFR

AF:

0.0103

AC:

0.0102631

AN:

0.0102631

Gnomad4 AMR

AF:

0.00184

AC:

0.00183582

AN:

0.00183582

Gnomad4 ASJ

AF:

0.000868

AC:

0.000868056

AN:

0.000868056

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000414

AC:

0.000413907

AN:

0.000413907

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000443

AC:

0.0000442974

AN:

0.0000442974

Gnomad4 OTH

AF:

0.00237

AC:

0.00237192

AN:

0.00237192

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000685

Hom.:

Bravo

AF:

0.00346

ESP6500AA

AF:

0.00149

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000418

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:8

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 24, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FKRP c.822C>G (p.Ile274Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 114982 control chromosomes, predominantly at a frequency of 0.0096 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0024). To our knowledge, no occurrence of c.822C>G in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 129058). Based on the evidence outlined above, the variant was classified as likely benign. -

Dec 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2023

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

May 20, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27142102) -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Jun 05, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 26, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Walker-Warburg congenital muscular dystrophy

Benign:1

Feb 03, 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

0.32

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.59

DEOGEN2

Uncertain

0.52

D;D

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.45

.;T

MetaRNN

Benign

0.0068

T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

-0.29

N;N

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.043

D;D

Sift4G

Benign

0.061

T;T

Polyphen

0.0080

B;B

Vest4

0.28

MVP

0.83

MPC

0.65

ClinPred

0.0077

GERP RS

1.8

Varity_R

0.55

gMVP

0.86

Mutation Taster

=79/21

polymorphism

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