1-6593388-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_014851.4(KLHL21):c.1771C>T(p.Arg591Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000025 in 1,602,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
KLHL21
NM_014851.4 missense
NM_014851.4 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 4.42
Genes affected
KLHL21 (HGNC:29041): (kelch like family member 21) Enables cullin family protein binding activity. Contributes to ubiquitin-protein transferase activity. Involved in chromosome passenger complex localization to spindle midzone; protein ubiquitination; and regulation of cytokinesis. Located in polar microtubule. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23153707).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL21 | NM_014851.4 | c.1771C>T | p.Arg591Trp | missense_variant | 4/4 | ENST00000377658.8 | |
KLHL21 | NM_001324309.2 | c.*720C>T | 3_prime_UTR_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL21 | ENST00000377658.8 | c.1771C>T | p.Arg591Trp | missense_variant | 4/4 | 1 | NM_014851.4 | P1 | |
KLHL21 | ENST00000496707.5 | c.670C>T | p.Arg224Trp | missense_variant | 4/4 | 1 | |||
KLHL21 | ENST00000377663.3 | c.*1977C>T | 3_prime_UTR_variant | 3/3 | 1 | ||||
KLHL21 | ENST00000467612.5 | c.670C>T | p.Arg224Trp | missense_variant | 4/4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000829 AC: 2AN: 241342Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 131876
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GnomAD4 exome AF: 0.0000248 AC: 36AN: 1449944Hom.: 0 Cov.: 31 AF XY: 0.0000305 AC XY: 22AN XY: 720518
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74350
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2023 | The c.1771C>T (p.R591W) alteration is located in exon 4 (coding exon 4) of the KLHL21 gene. This alteration results from a C to T substitution at nucleotide position 1771, causing the arginine (R) at amino acid position 591 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.
REVEL
Benign
Sift
Uncertain
D;.;.;.
Sift4G
Uncertain
D;D;D;.
Polyphen
D;.;.;.
Vest4
MutPred
Loss of solvent accessibility (P = 6e-04);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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