19-46756420-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_024301.5(FKRP):ā€‹c.970G>Cā€‹(p.Glu324Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000317 in 1,577,982 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 Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000028 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

7
6
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.29
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 Uncertain_significance. Variant got 5 ACMG points.

PM1
In a helix (size 20) in uniprot entity FKRP_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_024301.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FKRPNM_024301.5 linkc.970G>C p.Glu324Gln 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 linkc.970G>C p.Glu324Gln missense_variant 4/41 NM_024301.5 ENSP00000326570.4 Q9H9S5
FKRPENST00000391909.7 linkc.970G>C p.Glu324Gln missense_variant 4/42 ENSP00000375776.2 Q9H9S5
FKRPENST00000597339.5 linkn.247-5413G>C intron_variant 5
FKRPENST00000600646.5 linkn.247+7755G>C intron_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151896
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000280
AC:
4
AN:
1426086
Hom.:
0
Cov.:
32
AF XY:
0.00000425
AC XY:
3
AN XY:
705788
show subpopulations
Gnomad4 AFR exome
AF:
0.0000303
Gnomad4 AMR exome
AF:
0.0000522
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:
9.13e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151896
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74200
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 28, 2023Variant summary: FKRP c.970G>C (p.Glu324Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182402 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.970G>C has been reported in the literature in one individual affected with FKRP-related myopathy (Lubieniecki_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Autosomal recessive limb-girdle muscular dystrophy type 2I Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.May 04, 2021- -
Walker-Warburg congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 03, 2022This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 324 of the FKRP protein (p.Glu324Gln). This variant is not present in population databases (gnomAD no frequency). 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: 1039237). 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: "Tolerated"; 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
0.24
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T;T
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
.;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.3
M;M
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.3
N;N
REVEL
Pathogenic
0.82
Sift
Benign
0.031
D;D
Sift4G
Uncertain
0.045
D;D
Polyphen
1.0
D;D
Vest4
0.60
MutPred
0.36
Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);
MVP
0.98
MPC
1.6
ClinPred
0.92
D
GERP RS
4.2
Varity_R
0.56
gMVP
0.86

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: rs886044183; hg19: chr19-47259677; COSMIC: COSV59359617; COSMIC: COSV59359617; API