1-6593523-G-A

Position:

• chr1-6593523-G-A

Variant summary

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

The NM_014851.4(KLHL21):​c.1636C>T​(p.Leu546Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHL21 NM_014851.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

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 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
KLHL21	NM_014851.4	c.1636C>T	p.Leu546Phe	missense_variant	4/4	ENST00000377658.8	NP_055666.2
KLHL21	NM_001324309.2	c.*585C>T		3_prime_UTR_variant	4/4		NP_001311238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL21	ENST00000377658.8	c.1636C>T	p.Leu546Phe	missense_variant	4/4	1	NM_014851.4	ENSP00000366886.4
KLHL21	ENST00000496707.5	c.535C>T	p.Leu179Phe	missense_variant	4/4	1		ENSP00000468710.1
KLHL21	ENST00000377663.3	c.*1842C>T		3_prime_UTR_variant	3/3	1		ENSP00000366891.3
KLHL21	ENST00000467612.5	c.535C>T	p.Leu179Phe	missense_variant	4/4	3		ENSP00000466089.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 10, 2024

The c.1636C>T (p.L546F) 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 1636, causing the leucine (L) at amino acid position 546 to be replaced by a phenylalanine (F). 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	D;.;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0060	D;.;.
Sift4G	Uncertain	0.013	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.60
MutPred		0.70		Loss of catalytic residue at L546 (P = 0.1088);.;.;
MVP		0.91
MPC		0.91
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.49
gMVP		0.58

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: rs1393438240; hg19: chr1-6653583;