rs770711331

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_024301.5(FKRP):​c.266C>T​(p.Pro89Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000913 in 1,424,412 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P89A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000091 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

15
2
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.77
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-46755715-C-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
Variant 19-46755716-C-T is Pathogenic according to our data. Variant chr19-46755716-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755716-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FKRPNM_024301.5 linkuse as main transcriptc.266C>T p.Pro89Leu missense_variant 4/4 ENST00000318584.10 NP_077277.1 Q9H9S5A0A024R0R7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FKRPENST00000318584.10 linkuse as main transcriptc.266C>T p.Pro89Leu missense_variant 4/41 NM_024301.5 ENSP00000326570.4 Q9H9S5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000154
AC:
3
AN:
195042
Hom.:
0
AF XY:
0.0000187
AC XY:
2
AN XY:
106826
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000347
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000913
AC:
13
AN:
1424412
Hom.:
0
Cov.:
33
AF XY:
0.00000848
AC XY:
6
AN XY:
707232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000241
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000909
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000168
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylMar 07, 2017- -
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 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 09, 2021- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJul 30, 2021- -
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 27, 2024- -
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 04, 2023This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the FKRP protein (p.Pro89Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with muscular dystrophy (PMID: 16368217, 17446099, 18639457, 18691338). ClinVar contains an entry for this variant (Variation ID: 551007). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FKRP protein function with a positive predictive value of 95%. This variant disrupts the p.Pro89 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been observed in individuals with FKRP-related conditions (PMID: 15833426, 17113772), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
.;D;D;.;.;.;.;T
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.45
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.7
.;L;L;.;.;.;.;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-6.6
.;D;D;.;.;.;.;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
.;D;D;.;.;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D
Polyphen
1.0
.;D;D;.;.;.;.;.
Vest4
0.62, 0.72
MutPred
0.85
Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);Loss of glycosylation at P89 (P = 0.0197);
MVP
0.96
MPC
1.5
ClinPred
0.97
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.89
gMVP
0.81

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.

Other links and lift over

dbSNP: rs770711331; hg19: chr19-47258973; API