1-6593402-C-A

Variant names:

• chr1-6593402-C-A
• rs772932433
• NM_014851.4:c.1757G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014851.4(KLHL21):​c.1757G>T​(p.Arg586Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R586P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLHL21 NM_014851.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.645
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10294825).

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.1757G>T	p.Arg586Leu	missense	Exon 4 of 4	NP_055666.2
	KLHL21	NM_001324309.2		c.*706G>T		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.1757G>T	p.Arg586Leu	missense	Exon 4 of 4	ENSP00000366886.4	Q9UJP4-1
	KLHL21	ENST00000496707.5	TSL:1	c.656G>T	p.Arg219Leu	missense	Exon 4 of 4	ENSP00000468710.1	K7ESH2
	KLHL21	ENST00000377663.3	TSL:1	c.*1963G>T		3_prime_UTR	Exon 3 of 3	ENSP00000366891.3	Q9UJP4-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454250 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722832

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.00 AC: 0 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108558

Other (OTH) AF: 0.0000166 AC: 1 AN: 60070

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	3.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.65
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.061
Sift	Benign	0.034	D
Sift4G	Uncertain	0.012	D
Polyphen		0.45	B
Vest4		0.24
MutPred		0.30		Gain of catalytic residue at R586 (P = 0.025)
MVP		0.59
MPC		0.43
ClinPred		0.25	T
GERP RS		0.91
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.056
gMVP		0.38
Mutation Taster		=93/7	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: rs772932433; hg19: chr1-6653462;