rs766747690

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_024301.5(FKRP):c.511C>G(p.Leu171Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L171L) has been classified as Likely benign.

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:2

Conservation

PhyloP100: 0.608

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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_024301.5

PM2

Very rare variant in population databases, with high coverage;

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.37225312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.511C>G	p.Leu171Val	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.511C>G	p.Leu171Val	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

134224

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1386068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684634

African (AFR)

AF:

0.00

AC:

AN:

31406

American (AMR)

AF:

0.00

AC:

AN:

35868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25056

East Asian (EAS)

AF:

0.00

AC:

AN:

35900

South Asian (SAS)

AF:

0.00

AC:

AN:

79340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080470

Other (OTH)

AF:

0.00

AC:

AN:

57910

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000937

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 15, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The L171V variant of uncertain significance in the FKRP gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. L171V was not observed in approximately 5,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 4X), nor was it observed in the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations. The L171V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. And while this substitution occurs at a position that is highly conserved across species, V171 is the native amino acid residue in at least one species. Nevertheless, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. -

Walker-Warburg congenital muscular dystrophy

Uncertain:1

Sep 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine with valine at codon 171 of the FKRP protein (p.Leu171Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with FKRP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.75

.;T;T

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.37

T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.4

L;L;.

PhyloP100

0.61

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.3

N;N;.

REVEL

Pathogenic

0.66

Sift

Benign

0.13

T;T;.

Sift4G

Benign

0.15

T;T;D

Polyphen

0.63

P;P;.

Vest4

0.41

MutPred

0.30

Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);.;

MVP

0.68

MPC

1.6

ClinPred

0.74

GERP RS

2.4

Varity_R

0.34

gMVP

0.67

Mutation Taster

=60/40

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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