chr1-6599400-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014851.4(KLHL21):c.1074C>G(p.Ser358Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,220 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
KLHL21
NM_014851.4 missense
NM_014851.4 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: -0.733
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL21 | NM_014851.4 | c.1074C>G | p.Ser358Arg | missense_variant | 2/4 | ENST00000377658.8 | |
KLHL21 | NM_001324309.2 | c.1074C>G | p.Ser358Arg | missense_variant | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL21 | ENST00000377658.8 | c.1074C>G | p.Ser358Arg | missense_variant | 2/4 | 1 | NM_014851.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000244 AC: 6AN: 245564Hom.: 0 AF XY: 0.0000300 AC XY: 4AN XY: 133282
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461070Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22AN XY: 726786
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74314
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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 | Nov 07, 2022 | The c.1074C>G (p.S358R) alteration is located in exon 2 (coding exon 2) of the KLHL21 gene. This alteration results from a C to G substitution at nucleotide position 1074, causing the serine (S) at amino acid position 358 to be replaced by an arginine (R). 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
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Uncertain
D;T
Polyphen
D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);
MVP
MPC
ClinPred
T
GERP RS
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