1-6599090-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014851.4(KLHL21):c.1384G>A(p.Ala462Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000158 in 1,455,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KLHL21 NM_014851.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94

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]

ACMG classification

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=0.22136897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL21	NM_014851.4	c.1384G>A	p.Ala462Thr	missense_variant	2/4	ENST00000377658.8
KLHL21	NM_001324309.2	c.1384G>A	p.Ala462Thr	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL21	ENST00000377658.8	c.1384G>A	p.Ala462Thr	missense_variant	2/4	1	NM_014851.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000827 AC: 2 AN: 241846 Hom.: 0 AF XY: 0.00000764 AC XY: 1 AN XY: 130962

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: 0.00

Gnomad FIN exome AF: 0.0000478

Gnomad NFE exome AF: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1455938 Hom.: 0 Cov.: 30 AF XY: 0.0000180 AC XY: 13 AN XY: 723838

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: 0.0000117

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000568 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.1384G>A (p.A462T) 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 1384, causing the alanine (A) at amino acid position 462 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;T;T;.
Eigen	Benign	0.063
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.0	L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N;N;.;.;.
REVEL	Benign	0.066
Sift	Benign	0.17	T;T;.;.;.
Sift4G	Benign	0.15	T;T;T;.;T
Polyphen		0.024	B;P;.;.;.
Vest4		0.35
MutPred		0.52		Loss of catalytic residue at A462 (P = 0.0947);Loss of catalytic residue at A462 (P = 0.0947);.;.;.;
MVP		0.74
MPC		0.24
ClinPred		0.57	D
GERP RS		5.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.11
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1421059980; hg19: chr1-6659150; COSMIC: COSV66554141;