rs772447646

Variant names:

• chr1-6593447-C-T
• rs772447646
• NM_014851.4:c.1712G>A

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.1712G>A​(p.Arg571His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,352 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: KLHL21 NM_014851.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.682
• 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=0.07579997).

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.1712G>A	p.Arg571His	missense	Exon 4 of 4	NP_055666.2
	KLHL21	NM_001324309.2		c.*661G>A		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.1712G>A	p.Arg571His	missense	Exon 4 of 4	ENSP00000366886.4	Q9UJP4-1
	KLHL21	ENST00000496707.5	TSL:1	c.611G>A	p.Arg204His	missense	Exon 4 of 4	ENSP00000468710.1	K7ESH2
	KLHL21	ENST00000377663.3	TSL:1	c.*1918G>A		3_prime_UTR	Exon 3 of 3	ENSP00000366891.3	Q9UJP4-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 250564 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461014 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726832

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111916

Other (OTH) AF: 0.0000331 AC: 2 AN: 60372

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74506

African (AFR) AF: 0.0000481 AC: 2 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.68
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.085
Sift	Benign	0.15	T
Sift4G	Benign	0.56	T
Polyphen		0.0030	B
Vest4		0.084
MutPred		0.29		Gain of catalytic residue at R571 (P = 0.0781)
MVP		0.81
MPC		0.30
ClinPred		0.098	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.029
gMVP		0.30
Mutation Taster		=97/3	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: rs772447646; hg19: chr1-6653507;