chr1-6599420-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_014851.4(KLHL21):c.1054G>A(p.Val352Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,612,160 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 (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
KLHL21
NM_014851.4 missense
NM_014851.4 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 6.17
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 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.858
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL21 | NM_014851.4 | c.1054G>A | p.Val352Met | missense_variant | 2/4 | ENST00000377658.8 | |
KLHL21 | NM_001324309.2 | c.1054G>A | p.Val352Met | missense_variant | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL21 | ENST00000377658.8 | c.1054G>A | p.Val352Met | missense_variant | 2/4 | 1 | NM_014851.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000820 AC: 2AN: 243762Hom.: 0 AF XY: 0.00000755 AC XY: 1AN XY: 132434
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GnomAD4 exome AF: 0.00000822 AC: 12AN: 1459992Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6AN XY: 726180
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74334
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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 | Aug 23, 2021 | The c.1054G>A (p.V352M) alteration is located in exon 2 (coding exon 2) of the KLHL21 gene. This alteration results from a G to A substitution at nucleotide position 1054, causing the valine (V) at amino acid position 352 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;T
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.1866);Gain of MoRF binding (P = 0.1866);
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