rs750512280
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000284669.2(KLHL41):āc.1276A>Gā(p.Lys426Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,451,572 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
KLHL41
ENST00000284669.2 missense
ENST00000284669.2 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 7.16
Genes affected
KLHL41 (HGNC:16905): (kelch like family member 41) This gene is a member of the kelch-like family. The encoded protein contains a BACK domain, a BTB/POZ domain, and 5 Kelch repeats. This protein is thought to function in skeletal muscle development and maintenance. Mutations in this gene have been associated with nemaline myopathy (NM), a rare congenital muscle disorder. [provided by RefSeq, Mar 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KLHL41 | NM_006063.3 | c.1276A>G | p.Lys426Glu | missense_variant | 3/6 | ENST00000284669.2 | NP_006054.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KLHL41 | ENST00000284669.2 | c.1276A>G | p.Lys426Glu | missense_variant | 3/6 | 1 | NM_006063.3 | ENSP00000284669 | P1 | |
KLHL41 | ENST00000463400.1 | n.280A>G | non_coding_transcript_exon_variant | 3/5 | 3 | |||||
KLHL41 | ENST00000480330.5 | n.249A>G | non_coding_transcript_exon_variant | 3/3 | 4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000416 AC: 1AN: 240374Hom.: 0 AF XY: 0.00000770 AC XY: 1AN XY: 129854
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1451572Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2AN XY: 721846
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Nemaline myopathy 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 30, 2021 | This sequence change replaces lysine with glutamic acid at codon 426 of the KLHL41 protein (p.Lys426Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs750512280, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with KLHL41-related conditions. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M
MutationTaster
Benign
N;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;T
Sift4G
Uncertain
D;T
Polyphen
0.092
.;B
Vest4
MutPred
0.57
.;Loss of methylation at K426 (P = 0.0273);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at