1-6593396-C-G

Variant names:

• chr1-6593396-C-G
• rs143513148
• NM_014851.4:c.1763G>C

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.1763G>C​(p.Arg588Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,452,378 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R588Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (1 hom.)
• Consequence: KLHL21 NM_014851.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.279
• 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=0.112018675).

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.1763G>C	p.Arg588Pro	missense	Exon 4 of 4	NP_055666.2
	KLHL21	NM_001324309.2		c.*712G>C		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.1763G>C	p.Arg588Pro	missense	Exon 4 of 4	ENSP00000366886.4	Q9UJP4-1
	KLHL21	ENST00000496707.5	TSL:1	c.662G>C	p.Arg221Pro	missense	Exon 4 of 4	ENSP00000468710.1	K7ESH2
	KLHL21	ENST00000377663.3	TSL:1	c.*1969G>C		3_prime_UTR	Exon 3 of 3	ENSP00000366891.3	Q9UJP4-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243180 AF XY: 0.00000753

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452378 Hom.: 1 Cov.: 31 AF XY: 0.00000693 AC XY: 5 AN XY: 721832

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 43952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107722

Other (OTH) AF: 0.00 AC: 0 AN: 59994

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.28
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.12
Sift	Benign	0.063	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.0	B
Vest4		0.17
MutPred		0.31		Gain of glycosylation at R588 (P = 0.0142)
MVP		0.54
MPC		0.63
ClinPred		0.48	T
GERP RS		0.77
Varity_R		0.22
gMVP		0.75
Mutation Taster		=79/21	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: rs143513148; hg19: chr1-6653456;