rs752663857

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001079802.2(FKTN):ā€‹c.124A>Gā€‹(p.Lys42Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,206 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 Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000020 ( 0 hom. )

Consequence

FKTN
NM_001079802.2 missense

Scores

7
12

Clinical Significance

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

Conservation

PhyloP100: 4.40
Variant links:
Genes affected
FKTN (HGNC:3622): (fukutin) The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3381403).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FKTNNM_001079802.2 linkuse as main transcriptc.124A>G p.Lys42Glu missense_variant 4/11 ENST00000357998.10 NP_001073270.1 O75072-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FKTNENST00000357998.10 linkuse as main transcriptc.124A>G p.Lys42Glu missense_variant 4/115 NM_001079802.2 ENSP00000350687.6 O75072-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
32
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251288
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135822
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:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000199
AC:
29
AN:
1460878
Hom.:
0
Cov.:
29
AF XY:
0.0000303
AC XY:
22
AN XY:
726840
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:
0.000325
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152328
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74486
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:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000111
Hom.:
0
ExAC
AF:
0.0000165
AC:
2
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

Walker-Warburg congenital muscular dystrophy Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Oct 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 19, 2022This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 42 of the FKTN protein (p.Lys42Glu). This variant is present in population databases (rs752663857, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FKTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 578333). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 04, 2024The p.K42E variant (also known as c.124A>G), located in coding exon 2 of the FKTN gene, results from an A to G substitution at nucleotide position 124. The lysine at codon 42 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.092
T
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;T;.;.
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.82
.;T;.;T
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.34
T;T;T;T
MetaSVM
Uncertain
0.38
D
MutationAssessor
Benign
1.7
L;L;L;L
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-0.91
.;N;N;N
REVEL
Uncertain
0.41
Sift
Uncertain
0.026
.;D;D;D
Sift4G
Benign
0.20
T;T;T;T
Polyphen
0.18
B;B;.;.
Vest4
0.49
MutPred
0.28
Gain of ubiquitination at K44 (P = 0.0104);Gain of ubiquitination at K44 (P = 0.0104);Gain of ubiquitination at K44 (P = 0.0104);Gain of ubiquitination at K44 (P = 0.0104);
MVP
0.81
MPC
0.15
ClinPred
0.17
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs752663857; hg19: chr9-108358897; API