1-6599242-G-A

Position:

• chr1-6599242-G-A

Variant summary

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

The NM_014851.4(KLHL21):​c.1232C>T​(p.Pro411Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHL21 NM_014851.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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.1232C>T	p.Pro411Leu	missense_variant	2/4	ENST00000377658.8	NP_055666.2
KLHL21	NM_001324309.2	c.1232C>T	p.Pro411Leu	missense_variant	2/4		NP_001311238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL21	ENST00000377658.8	c.1232C>T	p.Pro411Leu	missense_variant	2/4	1	NM_014851.4	ENSP00000366886.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

May 05, 2023

The c.1232C>T (p.P411L) alteration is located in exon 2 (coding exon 2) of the KLHL21 gene. This alteration results from a C to T substitution at nucleotide position 1232, causing the proline (P) at amino acid position 411 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.0	D;D;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.16	T;T;.;.;.
Sift4G	Benign	0.061	T;T;T;.;T
Polyphen		0.42	B;D;.;.;.
Vest4		0.82
MutPred		0.46		Loss of disorder (P = 0.123);Loss of disorder (P = 0.123);.;.;.;
MVP		0.88
MPC		0.32
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.30
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6659302;