NM_014851.4:c.1699T>G

Variant names:

• chr1-6593460-A-C
• rs748454656
• NM_014851.4:c.1699T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014851.4(KLHL21):​c.1699T>G​(p.Phe567Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F567S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHL21 NM_014851.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.595
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051271647).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014851.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL21	NM_014851.4	MANE Select	c.1699T>G	p.Phe567Val	missense	Exon 4 of 4	NP_055666.2
	KLHL21	NM_001324309.2		c.*648T>G		3_prime_UTR	Exon 4 of 4	NP_001311238.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL21	ENST00000377658.8	TSL:1 MANE Select	c.1699T>G	p.Phe567Val	missense	Exon 4 of 4	ENSP00000366886.4	Q9UJP4-1
	KLHL21	ENST00000496707.5	TSL:1	c.598T>G	p.Phe200Val	missense	Exon 4 of 4	ENSP00000468710.1	K7ESH2
	KLHL21	ENST00000377663.3	TSL:1	c.*1905T>G		3_prime_UTR	Exon 3 of 3	ENSP00000366891.3	Q9UJP4-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.59
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.045
Sift	Benign	0.23	T
Sift4G	Benign	0.45	T
Polyphen		0.0020	B
Vest4		0.054
MutPred		0.31		Loss of catalytic residue at Q565 (P = 0.0888)
MVP		0.40
MPC		0.32
ClinPred		0.034	T
GERP RS		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.047
gMVP		0.31
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs748454656; hg19: chr1-6653520;